Benzimidazolone derivatives

ABSTRACT

This invention relates to compounds and methods for the treatment of a condition mediated by CB1 receptor activity in a mammalian subject including a human, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the compound of formula (I) or pharmaceutically acceptable salts thereof, wherein: A, B, R 1 , R 2  and R 3  are each as described herein. These compounds are useful in the treatment of a condition mediated by CB2 receptor binding activity such as, but not limited to, inflammatory pain, nociceptive pain, neuropathic pain, fibromyalgia, chronic low back pain, visceral pain, acute cerebral ischemia, pain, chronic pain, acute pain, post herpetic neuralgia, neuropathies, neuralgia, diabetic neuropathy, HIV-related neuropathy, nerve injury, rheumatoid arthritic pain, osteoarthritic pain, back pain, cancer pain, dental pain, fibromyalgia, neuritis, sciatica, inflammation, neurodegenerative disease, spasticity, epilepsy, Tourette&#39;s syndrome, Parkinson&#39;s disease, neuroprotection, anxiety, cough, broncho constriction, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), colitis, cerebrovascular ischemia, cachexia, nausea, emesis, chemotherapy-induced emesis, rheumatoid arthritis, asthma, Crohn&#39;s disease, ulcerative colitis, asthma, dermatitis, seasonal allergic rhinitis, gastroesophageal reflux disease (GERD), constipation, diarrhea, functional gastrointestinal disorder, cutaneous T cell lymphoma, multiple sclerosis, osteoarthritis, psoriasis, systemic lupus erythematosus, diabetes, glaucoma, osteoporosis, glomerulonephritis, renal ischemia, nephritis, hepatitis, cerebral stroke, vasodialation, hypertension, vasculitis, myocardial infarction, cerebral ischemia, reversible airway obstruction, adult respiratory disease syndrome, chronic obstructive pulmonary disease (COPD), cryptogenic fibrosing alveolitis and bronchitis.

BACKGROUND OF THE INVENTION

This invention relates to benzimidazolone derivatives. These compoundshave cannabinoid CB1 receptor binding activity. The present inventionrelates to methods of treatment and use, comprising the abovederivatives for the treatment of disease conditions mediated by CB1receptor binding activity.

Cannabinoid receptors, endogenous cannabinoids and the enzymes thatsynthesize and degrade endocannabinoids make up the endocannabinoidsystem. CB1 and CB2 are two subtypes of cannabinoid receptors. CB1 andCB2 are both G protein coupled receptors. CB1 receptors primarily existin the central nervous system, but are also found in some peripheraltissues including pituitary gland, immune cells, reproductive tissues,gastrointestinal tissues, sympathetic ganglia, heart, lung, urinarybladder and adrenal gland. CB2 receptors primarily exist in immunecells. Cannabinoid agonists are believed to be useful in the treatmentof inflammatory pain, nociceptive pain, neuropathic pain, fibromyalgia,chronic low back pain, visceral pain, acute cerebral ischemia, pain,chronic pain, acute pain, post herpetic neuralgia, neuropathies,neuralgia, diabetic neuropathy, HIV-related neuropathy, nerve injury,rheumatoid arthritic pain, osteoarthritic pain, back pain, cancer pain,dental pain, fibromyalgia, neuritis, sciatica, inflammation,neurodegenerative disease, spasticity, epilepsy, Tourette's syndrome,Parkinson's disease, neuroprotection, anxiety, cough, bronchoconstriction, irritable bowel syndrome (IBS), inflammatory bowel disease(IBD), colitis, cerebrovascular ischemia, cachexia, nausea, emesis,chemotherapy-induced emesis, rheumatoid arthritis, asthma, Crohn'sdisease, ulcerative colitis, asthma, dermatitis, seasonal allergicrhinitis, gastroesophageal reflux disease (GERD), constipation,diarrhea, functional gastrointestinal disorder, cutaneous T celllymphoma, multiple sclerosis, osteoarthritis, psoriasis, systemic lupuserythematosus, diabetes, glaucoma, osteoporosis, glomerulonephritis,renal ischemia, nephritis, hepatitis, cerebral stroke, vasodialation,hypertension, vasculitis, myocardial infarction, cerebral ischemia,reversible airway obstruction, adult respiratory disease syndrome,chronic obstructive pulmonary disease (COPD), cryptogenic fibrosingalveolitis and bronchitis (See Annu. Rev. Pharmacol. Toxicol. (2006)46:101-22; Clinical Neuroscience Research (2005)5 185-199;Prostaglandins, Leukotrienes and Essential Fatty Acids (2002) 66(2&3),101-121.)

Some cannabinoid agonists exhibit high affinity for both CB1 and CB2receptors. Some CB agonists show a higher affinity for one of the CB1 orCB2 receptors. Compounds that have selective CB2 receptor bindingactivity may also have CB1 receptor binding activity and therefore maybe useful in the treatment of CB1 mediated disorders. In thealternative, Compounds that have selective CB1 receptor binding activitymay also have CB2 receptor binding activity and therefore may be usefulin the treatment of CB2 mediated disorders.

Some of the compounds of this invention are described inPCT/IB06/000521, filed Mar. 2, 2006, which is herein incorporated byreference.

There is a need to provide new CB1 ligands that are good drugcandidates. They should be well absorbed from the gastrointestinaltract, be metabolically stable and possess favorable pharmacokineticproperties. Furthermore, the Ideal drug candidate will exist in aphysical form that is stable, non-hygroscopic and easily formulated.

SUMMARY OF THE INVENTION

In this Invention, it has now been found out that the new class ofbenzimidazolone compounds show CB1 receptor binding activity andfavorable properties as drug candidates, and thus are useful for thetreatment of disease conditions mediated by CB1 binding activity such asinflammatory pain, nociceptive pain, neuropathic pain, fibromyalgia,chronic low back pain, visceral pain, acute cerebral ischemia, pain,chronic pain, acute pain, post herpetic neuralgia, neuropathies,neuralgia, diabetic neuropathy, HIV-related neuropathy, nerve injury,rheumatoid arthritic pain, osteoarthritic pain, back pain, cancer pain,dental pain, fibromyalgia, neuritis, sciatica, inflammation,neurodegenerative disease, spasticity, epilepsy, Tourette's syndrome,Parkinson's disease, neuroprotection, anxiety, cough, bronchoconstriction, irritable bowel syndrome (IBS), inflammatory bowel disease(IBD), colitis, cerebrovascular ischemia, cachexia, nausea, emesis,chemotherapy-induced emesis, rheumatoid arthritis, asthma, Crohn'sdisease, ulcerative colitis, asthma, dermatitis, seasonal allergicrhinitis, gastroesophageal reflux disease (GERD), constipation,diarrhea, functional gastrointestinal disorder, cutaneous T celllymphoma, multiple sclerosis, osteoarthritis, psoriasis, systemic lupuserythematosus, diabetes, glaucoma, osteoporosis, glomerulonephritis,renal Ischemia, nephritis, hepatitis, cerebral stroke, vasodialation,hypertension, vasculitis, myocardial Infarction, cerebral ischemia,reversible airway obstruction, adult respiratory disease syndrome,chronic obstructive pulmonary disease (COPD), cryptogenic fibrosingalveolitis and bronchitis (hereinafter, referred as ‘CB1 Diseases’).

The present invention provides a method for the treatment of a conditionmediated by CB1 receptor activity in a mammalian subject including ahuman, which comprises administering to a mammal in need of suchtreatment a therapeutically effective amount of the compound of formula(I):

or a pharmaceutically acceptable salt thereof, wherein:

A is a carbon atom or a nitrogen atom;

B is a carbon atom or a nitrogen atom;

R¹ is a C₁-C₄ alkyl group substituted with 1 to 3 substituentsindependently selected from the group consisting of a halo group, aC₁-C₄ alkyl group; a hydroxy group; a C₁-C₄ alkoxy group; a mercaptgroup; a C₁-C₄ alkylthio group; a C₁-C₄ alkylsulfinyl group; a C₁-C₄alkylsulfonyl group; an amino group; a C₁-C₄ alkylamino group; adi(C₁-C₄ alkyl)amino group; a (C₁-C₄ alkyl)(C₁-C₄ alkylsulfonyl)aminogroup; a cycloalkyl group; a cycloalkyl group substituted with 1 to 3substituents selected from the group consisting of a hydroxy group, aC₁-C₄ alkoxy group and a C₁-C₄ alkyl group; a heterocyclyl group; aheterocyclyl group substituted with 1 to 3 substituents selected fromthe group consisting of a hydroxy group, a C₁-C₄ alkoxy group, a C₁-C₄alkyl group and an oxo group; a cyano group; a heteroaryl group and aC₁-C₄ alkyl heteroaryl group;

R² is a cycloalkyl group; a cycloalkyl group substituted with 1 to 4substituents selected from the group consisting of a hydroxy group, aC₁-C₄ hydroxyalkyl group, a C₁-C₄ alkoxy group, a C₆-C₁₀ aryloxy group,a mercapt group, a C₁-C₄ alkylthio group, a C₆-C₁₀ arylthio group, acarboxy group, a C₁-C₄ alkoxy-carbonyl group, a C₁-C₄ alkyl group, aC₂-C₄ alkenyl group, a C₂-C₄ alkynyl group and an amino-carbonyl group;a C₆-C₁₀ aryl group; a C₆-C₁₀ aryl group substituted with 1 to 3substituents selected from the group consisting of a hydroxy group and aC₁-C₄ alkyl group; a heterocyclyl group; a heterocyclyl groupsubstituted with 1 to 3 substituents selected from the group consistingof a hydroxy group and a C₁-C₄ alkyl group; a C₁-C₁₀ alkyl group; or aC₁-C₁₀ alkyl group substituted with 1 to 3 substituents independentlyselected from the group consisting of a cyano group, a hydroxy group, atrifluoromethyl group, a C₂-C₄ alkenyl group, a C₂-C₄ alkynyl group, aC₁-C₄ alkoxy group, a C₆-C₁₀ aryloxy group, a mercapt group, a C₁-C₄alkylthio group, a C₁-C₄ alkylsulfinyl group, a C₁-C₄ alkylsulfonylgroup, a C₁-C₄ alkylsulfonylamino group, a C₆-C₁₀ arylthio group, acarboxy group, a C₁-C₄alkyl-carbonyl group, a trifluoromethyl-carbonylgroup, a C₁-C₄ alkoxy-carbonyl group, an amino carbonyl group, a C₁-C₄alkylamino-carbonyl group, a C₁-C₄ hydroxyalkylamino-carbonyl group, adi(C₁-C₄ alkyl)amino-carbonyl group, a (C₁-C₄ hydroxyalkyl)(C₁-C₄alkyl)amino-carbonyl group, a heterocyclyl-carbonyl group, a cycloalkylgroup, a heterocyclyl group, a C₁-C₄ alkyl-substituted heterocyclylgroup, a C₆-C₁₀ aryl group, a di(C₁-C₄ alkyl)amino group, a C₁-C₄alkoxyC₁-C₄ alkylamino-carbonyl group, an aryl C₁-C₄alkylamino-carbonyl group,and a heteroaryl C₁-C₄ alkylamino-carbonyl group and

R³ is a hydrogen atom, a halogen atom, a hydroxy group, a C₁-C₄ alkylgroup, a C₁-C₄ haloalkyl group, a C₁-C₄ alkoxy group, a C₁-C₄ alkylthiogroup, a C₁-C₄ alkylsulfonyl group, a C₁-C₄ alkylsulfinyl group or anaminosulfonyl group.

The present invention is also directed to a compound or pharmaceuticallyacceptable salt thereof of formula (I) wherein:

A is a carbon atom or a nitrogen atom;

B is a carbon atom or a nitrogen atom;

R¹ is selected from the group consisting of H, CH₃—(CH₂)₄—, CH₃—(CH₂)₃—,cyano-(CH₂)₃—, cyano-(CH₂)₄—, CF₃—(CH₂)₂—, cyclobutyl-CH₂—,cyclobutyl-(CH₂)₂—, cyclopropyl-(CH₂)₃—, cyclopropyl-C(O)CH₂—,CH₃—CH₂—NH—C(O)CH₂—, (CH₃)₃—C—C(O)CH₂—, cyclohexyl-CH₂—,OH-cyclohexyl-CH₂—, F₂-cyclohexyl-CH₂—, F₂-cyclohexenyl-CH₂—,tetrahydrofuranyl-CH₂—, tetrahydropyranyl-CH₂—, fluoro-benzyl,CH₃—O-benzyl, cyano-benzyl, methyl-benzyl, chloro-benzyl,oxo-tetrahydrofuranyl-CH₂—, oxo-pyrrolidinyl-CH₂—, pyridinyl-CH₂—,pyrazinyl-CH₂—, pyrimidinyl-CH₂—, CH₃-pyrazolyl-CH₂—, CH₃-oxazolyl-CH₂—,CH₃-isoxazolyl-CH₂—, CH₃-oxadiazolyl-CH₂—, CH₃-thiazolyl-CH₂—, andCH₃-thiadiazolyl-CH₂—;

R² is selected from the group consisting of H, NR⁴R⁵—C(O)—CR⁶R⁷—,CR⁶R⁹R¹⁰—, (CH₃)₂—N—CH₂—C(CH₃)₂—CH₂—, tetrahydronaphthalenyl,OH-dihydroindenyl, OH-cyclohexyl, CH₃—CH₂-pyrrolidinyl-CH₂—,oxadiazolyl-CR¹¹R¹²— optionally substituted with CH₃, NH₂,(CH₃)₂—N—C(O)—, CH₃—NH—C(O), tetrahydronaphthalenyl-NH—C(O)—,azepanyl-C(O)—, oxopyrrolidinyl-(CH₂)₃—NH—C(O)—, CH₃O—CH₂)₂—NH—C(O)—,OH-cyclohexyl-NH—C(O)—, OH—CH₂-piperidinyl-C(O)—, CH₃—CH₂—,(CH₃)₂—CH—(CH₂)₂—NH—C(O)—, or (CH₃)₂—CH—; isoxazolyl-CR¹¹R¹²— optionallysubstituted with CH₃; furyl-CR¹¹R¹²— optionally substituted with CH₃ orCF₃; pyrazolyl-CR¹¹R¹²— optionally substituted with CH₃, (CH₃)₂—CH—, orCH₃—CH₂—; thiazolyl-CR¹¹R¹²— optionally substituted with CH₃, CH₃—CH₂—,or CF₃; and dihydroisochromenyl-CR¹¹R¹²—;

R³ is selected from the group consisting of H, F, Cl, bromo, difluoro,methyl, cyano, methoxy, trifluoromethyl, methylthio, methylsulfinyl,methylsulfonyl and aminosulfonyl;

R⁴ and R⁵ are H, OH—(CH₂)₂—, NH₂—C(O)—(CH₂)₂—, CH₃—O—(CH₂)₂—, benzyl,pyridinyl, cyclobutyl, (CH₃)₃—C—, cyclopropyl, CH₃, OH—(CH₂)₃—, or(OH)₂—CH₂—CH—CH₂—;

R⁶ and R⁷ are H, (CH₃)₃—C—, CH₃, benzyl, phenyl, tetrahydropyranyl,cyclohexyl, (CH₃)₂—CH—CH₂—, (CH₃)₂—CH—, or (OH)(CH₃)—CH—;

R⁸, R⁹ and R¹⁰ are H, (CH₃)₃—C—, NH₂—C(O)—, OH—CH₂—, (CH₃CH₂)₂—N—CH₂—,CH₃, (OH) (CH₃)₂—CH—, CH₃—NH—C(O)—CH₂—, cyclopropyl-NH—C(O)CH₂—,NH₂—C(O)—CH₂—NH—C(O)—CH₂—, or COOH—CH₂—; or two of R⁸, R⁹, or R¹⁰ form acyclohexyl, and

R¹¹ and R¹² are H, CH₃, or (CH₃)₃C—.

Also, the present invention is directed to the method for the treatmentof a condition mediated by CB1 receptor activity in a mammalian subjectincluding a human, which comprises administering to a mammal in need ofsuch treatment a therapeutically effective amount of a compound offormula (I) as described in the immediately preceeding paragraph.

Also, the present invention provides the use of a compound of formula(I) or a pharmaceutically acceptable salt thereof, each as describedherein, for the manufacture of a medicament for the treatment of acondition mediated by CB1 receptor binding activity.

Also, the present invention also provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof, each asdescribed herein, for the manufacture of a medicament for the treatmentof diseases selected from CB1 Diseases.

The compounds of the present invention may show less toxicity, goodabsorption, distribution, good solubility, less protein binding affinityother than CB1 receptor, less drug-drug interaction, and good metabolicstability.

DETAILED DESCRIPTION OF THE INVENTION

The method of the present invention comprises administering to a mammalin need of such treatment a therapeutically effective amount of thecompound or a pharmaceutically acceptable salt thereof wherein:

A is a carbon atom or a nitrogen atom;

B is a carbon atom or a nitrogen atom;

R¹ is a C₁-C₄ alkyl group substituted with 1 to 3 substituentsindependently selected from the group consisting of a C₁-C₄ alkyl group;a hydroxy group; a C₁-C₄ alkoxy group; a mercapt group; a C₁-C₄alkylthio group; a C₁-C₄ alkylsulfinyl group; a C₁-C₄ alkylsulfonylgroup; an amino group; a C₁-C₄ alkylamino group; a di(C₁-C₄ alkyl)aminogroup; a (C₁-C₄ alkyl)(C₁-C₄ alkylsulfonyl)amino group; a cycloalkylgroup; a cycloalkyl group substituted with 1 to 3 substituents selectedfrom the group consisting of a hydroxy group, a C₁-C₄ alkoxy group and aC₁-C₄ alkyl group; a heterocyclyl group; and a heterocyclyl groupsubstituted with 1 to 3 substituents selected from the group consistingof a hydroxy group, a C₁-C₄ alkoxy group and a C₁-C₄ alkyl group;

R² is a cycloalkyl group; a cycloalkyl group substituted with 1 to 4substituents selected from the group consisting of a hydroxy group, aC₁-C₄ hydroxyalkyl group, a C₁-C₄ alkoxy group, a C₆-C₁₀ aryloxy group,a mercapt group, a C₁-C₄ alkylthio group, a C₆-C₁₀ arylthio group, acarboxy group, a C₁-C₄ alkoxy-carbonyl group, a C₁-C₄ alkyl group, aC₂-C₄ alkenyl group and a C₂-C₄ alkynyl group; a C₆-C₁₀ aryl group; aC₆-C₁₀ aryl group substituted with 1 to 3 substituents selected from thegroup consisting of a hydroxy group and a C₁-C₄ alkyl group; aheterocyclyl group; a heterocyclyl group substituted with 1 to 3substituents selected from the group consisting of a hydroxy group and aC₁-C₄ alkyl group; a C₁-C₁₀ alkyl group; or a C₁-C₁₀ alkyl groupsubstituted with 1 to 3 substituents independently selected from thegroup consisting of a cyano group, a hydroxy group, a trifluoromethylgroup, a C₂-C₄ alkenyl group, a C₂-C₄ alkynyl group, a C₁-C₄ alkoxygroup, a C₆-C₁₀ aryloxy group, a mercapt group, a C₁-C₄ alkylthio group,a C₁-C₄ alkylsulfinyl group, a C₁-C₄ alkylsulfonyl group, a C₁-C₄alkylsulfonylamino group, a C₆-C₁₀ arylthio group, a carboxy group, aC₁-C₄alkyl-carbonyl group, a trifluoromethyl-carbonyl group, a C₁-C₄alkoxy-carbonyl group, an amino carbonyl group, a C₁-C₄alkylamino-carbonyl group, a C₁-C₄ hydroxyalkylamino-carbonyl group, adi(C₁-C₄ alkyl)amino-carbonyl group, a (C₁-C₄ hydroxyalkyl)(C₁-C₄alkyl)amino-carbonyl group, a heterocyclyl-carbonyl group, a cycloalkylgroup, a heterocyclyl group, a C₁-C₄ alkyl-substituted heterocyclylgroup and a C₆-C₁₀ aryl group; and

R³ is a hydrogen atom, a halogen atom, a hydroxy group, a C₁-C₄ alkylgroup, C₁-C₄ haloalkyl group or a C₁-C₄ alkoxy group.

In another embodiment the method comprises compounds of formula (I) or apharmaceutically acceptable salt thereof, wherein:

A is a carbon atom or a nitrogen atom;

B is a carbon atom or a nitrogen atom;

R¹ is a C₁-C₄ alkyl group substituted with 1 to 3 substituentsindependently selected from the group consisting of a halo group, aC₁-C₄ alkyl group; a C₁-C₄ alkylthio group; a cyano group; a heteroarylgroup, a C₁-C₄ alkyl heteroaryl group; a cycloalkyl group; a cycloalkylgroup substituted with hydroxy group, a heterocyclyl group; and aheterocyclyl group substituted with an oxo group;

R² is a cycloalkyl group substituted with a hydroxy group or an aminocarbonyl group; a C₆-C₁₀ aryl group substituted with a hydroxy group; ora C₁-C₁₀ alkyl group substituted with 1 to 3 substituents independentlyselected from the group consisting of a hydroxy group, an amino carbonylgroup, a di(C₁-C₄ alkyl)amino group, a cycloalkyl group, a heterocyclylgroup, a C₁-C₄ alkyl-substituted heterocyclyl group, a C₆-C₁₀ arylgroup, a C₁-C₄ alkoxy C₁-C₄ alkylamino-carbonyl group, an aryl C₁-C₄alkylamino-carbonyl group, and a heteroaryl C₁-C₄ alkylamino-carbonylgroup;

R³ is a hydrogen atom, a halogen atom, a hydroxy group, a C₁-C₄ alkylgroup, a C₁-C₄ haloalkyl group, a C₁-C₄ alkoxy group, a C₁-C₄ alkylthiogroup, a C₁-C₄ alkylsulfonyl group, a C₁-C₄ alkylsulfinyl group or anaminosulfonyl group.

In another embodiment the method comprises the compounds of formula (I)or a pharmaceutically acceptable salt thereof, wherein A is a carbonatom and B is a carbon atom.

In another embodiment the CB1 mediated condition is selected from thegroup consisting of inflammatory pain, nociceptive pain, neuropathicpain, fibromyalgia, chronic low back pain, visceral pain, acute cerebralischemia, pain, chronic pain, acute pain, post herpetic neuralgia,neuropathies, neuralgia, diabetic neuropathy, HIV-related neuropathy,nerve injury, rheumatoid arthritic pain, osteoarthritic pain, back pain,cancer pain, dental pain, fibromyalgia, neuritis, sciatica,inflammation, neurodegenerative disease, spasticity, epilepsy,Tourette's syndrome, Parkinson's disease, neuroprotection, anxiety,cough, broncho constriction, irritable bowel syndrome (IBS),inflammatory bowel disease (IBD), colitis, cerebrovascular ischemia,cachexia, nausea, emesis, chemotherapy-induced emesis, rheumatoidarthritis, asthma, Crohn's disease, ulcerative colitis, asthma,dermatitis, seasonal allergic rhinitis, gastroesophageal reflux disease(GERD), constipation, diarrhea, functional gastrointestinal disorder,cutaneous T cell lymphoma, multiple sclerosis, osteoarthritis,psoriasis, systemic lupus erythematosus, diabetes, glaucoma,osteoporosis, glomerulonephritis, renal, ischemia, nephritis, hepatitis,cerebral stroke, vasodialation, hypertension, vasculitis, myocardialinfarction, cerebral ischemia, reversible airway obstruction, adultrespiratory disease syndrome, chronic obstructive pulmonary disease(COPD), cryptogenic fibrosing alveolitis and bronchitis.

In another embodiment, the present invention provides a method oftreatment of a condition mediated by CB1 receptor activity in amammalian subject including a human, which comprises administering to amammal in need of such treatment a therapeutically effective amount of acompound or pharmaceutically acceptable salt thereof selected from thegroup list above.

In one embodiment the CB1 Diseases are selected form the groupconsisting of neurodegenerative disease, spasticity, epilepsy,Tourette's syndrome, Parkinson's disease, neuroprotection, anxiety,cachexia, nausea, vasodialation and hypertension.

Another aspect of the invention provides for a compound of formula (I)or a pharmaceutically acceptable salt thereof, wherein:

A is a carbon atom or a nitrogen atom;

B is a carbon atom or a nitrogen atom;

R¹ is selected from the group consisting of H, CH₃—(CH₂)₄—,cyano-(CH₂)₃—, cyano-(CH₂)₄—, CF₃—(CH₂)₂—, cyclobutyl-CH₂—,cyclobutyl-(CH₂)₂—, cyclopropyl-(CH₂)—, cyclohexyl-CH₂—,OH-cyclohexyl-CH₂—, tetrahydrofuranyl-CH₂—, tetrahydropyranyl-CH₂—,oxo-tetrahydrofuranyl-CH₂—, oxo-pyrrolidinyl-CH₂—, pyridinyl-CH₂—,pyrazinyl-CH₂—, pyrimidinyl-CH₂—, CH₃-pyrazolyl-CH₂—, CH₃-oxazolyl-CH₂—,CH₃-isoxazolyl-CH₂—, CH₃-oxadiazolyl-CH₂— CH₃-thiazolyl-CH₂—, andCH₃-thiadiazolyl-CH₂—;

R² is selected from the group consisting of H, NR⁴R⁵—C(O)—CR⁶R⁷—,CR⁸R⁹R¹⁰—, (CH₃)₂—N—CH₂—C(CH₃)₂—CH₂—, tetrahydronaphthalenyl,OH-dihydroindenyl, OH-cyclohexyl, and CH₃—CH₂-pyrrolidinyl-CH₂—;

R³ is selected from the group consisting of H, F, Cl, methyl, cyano,methoxy, trifluoromethyl, methylthio, methylsulfinyl, methylsulfonyl andaminosulfonyl;

R⁴ and R⁵ are H, OH—(CH₂)₂—, NH₂—C(O)—(CH₂)₂—, CH₃—O—(CH₂)_(r), benzyl,or pyridinyl;

R⁶ and R⁷ are H, (CH₃)₃—C—, CH₃, benzyl, phenyl, tetrahydropyranyl, orcyclohexyl;

R⁸, R⁹ and R¹⁰ are H, (CH₃)₃—C—, NH₂—C(O)—, OH—CH₂—, (CH₃CH₂)₂—N—CH₂—,or CH₃; or two of R⁸, R⁹, or R¹⁰ form a cyclohexyl.

In another embodiment the compound a pharmaceutically acceptable saltthereof, wherein:

A is a carbon atom;

B is a carbon atom;

R¹ is selected from the group consisting of H, CH₃—(CH₂)₄—,cyano-(CH₂)₃—, cyano-(CH₂)₄—, CF₃—(CH₂)₂—, cyclobutyl-CH₂—,cyclobutyl-(CH₂)₂—, cyclopropyl-(CH₂)₃—, cyclohexyl-CH₂—,OH-cyclohexyl-CH₂—, tetrahydrofuranyl-CH₂—, tetrahydropyranyl-CH₂—,oxo-tetrahydrofuranyl-CH₂—, oxo-pyrrolidinyl-CH₂—, pyridinyl-CH₂—,pyrazinyl-CH₂—, pyrimidinyl-CH₂—, CH₃-pyrazolyl-CH₂—, CH₃-oxazolyl-CH₂—,CH₃-isoxazolyl-CH₂—, CH₃-oxadiazolyl-CH₂—, CH₃-thiazolyl-CH₂—, andCH₃-thiadiazolyl-CH₂—;

R² is selected from the group consisting of H, NR⁴R⁵—C(O)CR⁶R⁷—,CR⁸R⁹R¹⁰—, (CH₃)₂—N—CH₂—C(CH₃)₂—CH₂—, tetrahydronaphthalenyl,OH-dihydroindenyl, OH-cyclohexyl, and CH₃—CH₂-pyrrolidinyl-CH₂—;

R³ is selected from the group consisting of H, F, Cl, methyl, cyano,methoxy, trifluoromethyl, methylthio, methylsulfinyl, methylsulfonyl andaminosulfonyl;

R⁴ and R⁵ are H, OH—(CH₂)₂—, NH₂—C(O)—(CH₂)₂—, CH₃—O—(CH₂)₂—, benzyl, orpyridinyl;

R⁶ and R⁷ are H, (CH₃)₃—C—, CH₃, benzyl, phenyl, tetrahydropyranyl, orcyclohexyl;

R⁸, R⁹ and R¹⁰ are H, (CH₃)₃—C—, NH₂—C(O), OH—CH₂—, (CH₃CH₂)₂—N—CH₂—, orCH₃; or two of R⁸, R⁹, or R¹⁰ form a cyclohexyl.

In another embodiment the compound a pharmaceutically acceptable saltthereof, wherein R¹ is selected from the group consisting of

In another embodiment the compound or a pharmaceutically acceptable saltthereof, wherein R² is selected from the group consisting of

In another embodiment a method of treatment comprises administering to amammal in need of such treatment a therapeutically effective amount ofthe compoundN-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamideorN-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-4-methyl-3-[2-(methylthio)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamideor a pharmaceutically acceptable salt thereof.

In another embodiment the compound selected from the group consisting of

-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-lylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclohexylmethyl)-6-fluoro-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-6-chloro-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclohexylmethyl-6-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-6-cyano-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclohexylmethyl)-5-fluoro-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-5-chloro-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-5-cyano-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-2,2-dimethylpropyl]-3-(cyclohexylmethyl)-4-fluoro-2-oxo-2,3-di    hydro-1H-benzimidazole-1-carboxamide;-   N-[(1)-1-(aminocarbonyl)-2,2-dimethylpropyl]-4-chloro-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-cyclohexylmethyl)-4-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-4-cyano-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-(cyclohexylmethyl)-N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-(cyclobutylmethyl)-N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]-2-oxo-3-pentyl-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-(cyclohexylmethyl)-N-{[(2S)-1-ethylpyrrolidin-2-yl]methyl}-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-(cyclobutylmethyl)-N-{[(2S)-1-ethylpyrrolidin-2-yl]methyl}-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-{[(2S)-1-ethylpyrrolidin-2-yl]methyl}-2-oxo-3-penty-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-(cyclohexylmethyl)-N-[3-(dimethylamino)-2,2-dimethylpropyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-(cyclobutylmethyl)-N-[3-(dimethylamino    2,2-dimethylpropyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[3-(dimethylamino)-2,2-dimethylpropyl]-2-oxo-3-pentyl-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-(cyclohexylmethyl)-N-[2-(diethylamino)-1-methylethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-(cyclobutylmethyl)-N-[2-(diethylamino)-1-methylethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[2-(diethylamino)-1-methylethyl]-2-oxo-3-pentyl-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-(cyclohexylmethyl)-N-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-(cyclobutylmethyl)-N-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-2-oxo-3-pentyl-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-(cyclohexylmethyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-(cyclobutylmethyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S,2S)-2-hydroxycyclohexyl]-2-oxo-3-pentyl-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-(cyclohexylmethyl)-N-(trans    hydroxycyclohexyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-(cyclobutylmethyl)-N-(trans-4-hydroxycyclohexyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-(trans-4-hydroxycyclohexyl)-2-oxo-3-pentyl-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-(cyclohexylmethyl)-2-oxo-N-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-(cyclobutylmethyl)-2-oxo-N-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   2-oxo-3-pentyl-N-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclobutylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-pentyl-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-3-(cyclobutylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-2-oxo-3-pentyl-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-(cyclobutylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-(2-amino-1,1-dimethyl-2-oxoethyl)-2-oxo-3-pentyl-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[1-(aminocarbonyl)cyclohexyl]-2-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[1-(aminocarbonyl)cyclohexyl]-3-(cyclobutylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[1-(aminocarbonyl)cyclohexyl]-2-oxo-3-pentyl-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-2-amino-2-oxo-1-phenylethyl]-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-2-amino-2-oxo-1-phenylethyl]-3-(cyclobutylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-2-amino-2-oxo-1-phenylethyl]-2-oxo-3-pentyl-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-alpha-{[3(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}-L-phenylalaninamide;-   N-alpha-{[3-(cyclobutylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}-L-phenylalaninamide;-   N-alpha-[(2-oxo-3-pentyl-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]-L-phenylalaninamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(2-cyclobutylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-1-3(3-cyclopropylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-(pyridin-2-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-(pyridin-2-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-(pyrimidin-2-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-(pyridazin-3-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-(pyrimidin-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[(5-methylisoxazol-3-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[(5-methyl-1H-pyrazol-3-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[(1-methyl-1H-pyrazol-3-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[(2-methyl-1,3-oxazol-5-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[(2-methyl-1,3-thiazol-5-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-t-carboxamide;-   N-[(1S)-1-aminocarbonyl)-2,2-dimethylpropyl]-3-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(3-cyanopropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(4-cyanobutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-2-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-(tetrahydrofuran-2-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-(2-cyclobutylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-(3-cyanopropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-2-amino-2-oxo-1-phenylethyl]-2-oxo-3-(pyridin-2-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-2-amino-2-oxo-1-phenylethyl]-2-oxo-3-(pyrazin-2-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-2-amino-2-oxo-1-phenylethyl]-3-[(5-methylisoxazol-3-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-alpha-({3-[(1-methyl-1H-pyrazol-3-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}carbonyl)-L-phenylalaninamide;-   N-alpha-({3-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}carbonyl)-L-phenylalaninamide;-   N-alpha-({2-oxo-3-[(5-oxotetrahydrofuran-2-yl)methyl]-2,3-dihydro-1H-benzimidazol-1-yl}carbonyl)-L-phenylalaninamide;-   N-alpha-({2-oxo-3-[(5-oxopyrrolidin-2-yl)methyl]-2,3-dihydro-1H-benzimidazol-1-yl)carbon    yl}-L-phenylalaninamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclohexylmethyl)-4-methoxy-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclohexylmethyl)-5-methoxy-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl)-3-(cyclohexylmethyl)-2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-1-carboxamide;-   N-[(1S)-1-aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,6b]pyridine-1-carboxamide;-   N-[(1S)-2-amino-1-cyclohexyl-2-oxoethyl]-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-2-amino-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl]-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[(1-hydroxycyclohexyl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-(cyclohexylmethyl)-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-(cyclohexylmethyl)-N-[(1S)-1-{[(2-methoxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-{(1S)-1-[(benzylamino)carbonyl]-2,2-dimethylpropyl}-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-(cyclohexylmethyl)-N-[(1S)-2,2-dimethyl-1-{[(pyridin-2-ylmethyl)amino]carbonyl}propyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-{[3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}-3-methyl-L-valyl-beta-alaninamide;-   N-[(1S)-1-(aminocarbonyl-2,2-dimethylpropyl]-3-(cyclohexylmethyl)-5-(methylthio)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1    aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclohexylmethyl)-5(methylsulfinyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclohexylmethyl)-5-(methylsulfonyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-5-aminosulfonyl)-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;    and-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-(3,3,3-trifluoropropyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide,-   In another embodiment a compound of formula (I) or a    pharmaceutically acceptable salt thereof, wherein:

A is a carbon atom or a nitrogen atom;

B is a carbon atom or a nitrogen atom;

R¹ is selected from the group consisting of H, CH₃—(CH₂)₄—, CH₃—(CH₂)₃—,cyano-(CH₂)—, cyano-(CH₂)₄—, CF₃—(CH₂)₂—, cyclobutyl-CH₂—,cyclobutyl-(CH₂)₂—, cyclopropyl-CH₂)₃—, cyclopropyl-C(O)—CH₂—,CH₃—CH₂—NH—C(O)—CH₂—, (CH₃)₃—C—C(O)—CH₂—, cyclohexyl-CH₂—,OH-cyclohexyl-CH₂—, F₂-cyclohexyl-CH₂—, F-cyclohexenyl-CH₂—,tetrahydrofuranyl-CH₂—, tetrahydropyranyl-CH₂—, fluoro-benzyl,CH₃—O-benzyl, cyano-benzyl, methyl-benzyl, chloro-benzyl,oxo-tetrahydrofuranyl-CH₂—, oxo-pyrrolidinyl-CH₂—, pyridinyl-CH₂—,pyrazinyl-CH₂—, pyrimidinyl-CH₂—, CH₃-pyrazolyl-CH₂—, CH₃-oxazolyl-CH₂—,CH₃-isoxazolyl-CH₂—, CH₃-oxadiazolyl-CH₂—, CH₃-thiazolyl-CH₂—, andCH₃-thiadiazolyl-CH₂—;

R² is selected from the group consisting of H, NR⁴R⁵—C(O)—CR⁶R⁷—,CR⁸R⁹R¹⁰—, (CH₃)₂—N—CH₂—C(CH₃)₂—CH₂—, tetrahydronaphthalenyl,OH-dihydroindenyl, OH-cyclohexyl, CH₃—CH₂-pyrrolidinyl-CH₂—,oxadiazolyl-CR¹¹R¹²— optionally substituted with CH₃, NH₂,(CH₃)₂—N—C(O)—, CH₃—NH—C(O), tetrahydronaphthalenyl-NH—C(O)—,azepanyl-C(O)—, oxopyrrolidinyl-(CH₂)—NH—C(O)—, CH₃—O—(CH₂)₂—NH—C(O)—,OH-cyclohexyl-NH—C(O)—, OH—CH₂-piperidinyl-C(O)—, —CH₃—CH₂—,(CH₃)₂—CH—(CH₂)₂—NH—C(O)—, or (CH₃)₂—CH—; isoxazolyl-CR¹¹R¹²— optionallysubstituted with CH₃; furyl-CR¹¹R¹²— optionally substituted with CH₃ orCF₃; pyrazolyl-CR¹¹R¹²— optionally substituted with CH₃, (CH₃)₂—CH—, orCH₃—CH₂—; thiazolyl-CR¹¹R¹²— optionally substituted with CH₃, CH₃—CH₂—,or CF₃; and dihydroisochromenyl-CR¹¹R¹²—;

R³ is selected from the group consisting of H, F, Cl, bromo, difluoro,methyl, cyano, methoxy, trifluoromethyl, methylthio, methylsulfinyl,methylsulfonyl and aminosulfonyl;

R⁴ and R⁵ are H, OH—(CH₂)₂—, NH₂—C(O)—(CH₂)₂—, CH₃—O—(CH₂)₂—, benzyl,pyridinyl, cyclobutyl, (CH₃)₃—C—, cyclopropyl, CH₃, OH—(CH₂)₃—, or(OH)₂—CH₂—CH—CH₂—;

R⁶ and R⁷ are H, (CH₃)₃—C—, CH₃, benzyl, phenyl, tetrahydropyranyl,cyclohexyl, (CH₃)₂—CH—CH₂—, (CH₃)₂—CH—, or (OH)(CH₃)—CH—;

R⁸, R⁹ and R¹⁰ are H, (CH₃)₃—C—, NH₂—C(O)—, OH—CH₂—, (CH₃CH₂)₂—N—CH₂—,CH₃, (OH) (CH₃)₂—CH—, CH₃—NH—C(O)—CH₂—, cyclopropyl-NH—C(O)—CH₂—,NH₂—C(O)—CH₂—NH—C(O)—CH₂—, or COOH—CH₂—; or two of R⁸, R⁹, or R¹⁰ form acyclohexyl, and

R¹¹ and R¹² are H, CH₃, or (CH₃)₃—C—.

In another embodiment the compound or a pharmaceutically acceptable saltthereof, wherein:

A is a carbon atom;

B is a carbon atom;

R¹ is selected from the group consisting of H, CH₃—CH₂)₄—, CH₃—(CH₂)—,cyano-(CH₂)₃—, cyano-(CH₂)₄—, CF₃—(CH₂)₂—, cyclobutyl-CH₂—,cyclobutyl-(CH₂)₂—, cyclopropyl-(CH₂)₃—, cyclopropyl-C(O)—CH₂—,CH₃—CH₂—NH—C(O)—CH₂—, (CH₃)₃—C—C(O)—CH₂—, cyclohexyl-CH₂—,OH-cyclohexyl-CH₂—, F₂-cyclohexyl-CH₂—, F-cyclohexenyl-CH₂—,tetrahydrofuranyl-CH₂—, tetrahydropyranyl-CH₂—, fluoro-benzyl,CH₃—O-benzyl, cyano-benzyl, methyl-benzyl, chloro-benzyl,oxo-tetrahydrofuranyl-CH₂—, oxo-pyrrolidinyl-CH₂—, pyridinyl-CH₂—,pyrazinyl-CH₂—, pyrimidinyl-CH₂—, CH₃-pyrazolyl-CH₂—, CH₃-oxazolyl-CH₂—,CH₃-isoxazolyl-CH₂—, CH₃-oxadiazolyl-CH₂—, CH₃-thiazolyl-CH₂—, andCH₃-thiadiazolyl-CH₂—;

R² is selected from the group consisting of H, NR⁴R⁵—C(O)—CR⁶R⁷—,CR⁸R⁹R¹⁰—, (CH₃)₂—N—CH₂—C(CH₃)₂—CH₂—, tetrahydronaphthalenyl,OH-dihydroindenyl, OH-cyclohexyl, CH₃—CH₂-pyrrolidinyl-CH₂—,oxadiazolyl-CR¹¹R¹²— optionally substituted with CH₃, NH₂,(CH₃)₂—N—C(O)—, CH₃—NH—C(O)—, tetrahydronaphthalenyl-NH—C(O)—,azepanyl-C(O)—, oxopyrrolidinyl-CH₂)₃—NH—C(O)—, CH₃—O—(CH₂)₂—NH—C(O)—,OH-cyclohexyl-NH—C(O)—, OH—CH₂-piperidinyl-C(O)—, CH₃—CH₂—,(CH₃)₂—CH₃)₂—CH₂)₂—NH—C(O)—, or (CH₃)₂—CH—; isoxazolyl-CR¹¹R¹²—optionally substituted with CH₃; furyl-CR¹¹R¹²— optionally substitutedwith CH₃ or CF₃; pyrazolyl-CR¹¹R¹²— optionally substituted with CH₃,(CH₃)₂—CH—, or CH₃—CH₂—; thiazolyl-CR¹¹R¹²— optionally substituted withCH₃, CH₃—CH₂—, or CF₃; and dihydroisochromenyl-CR¹¹R¹²—;

R³ is selected from the group consisting of H, F, Cl, bromo, difluoro,methyl, cyano, methoxy, trifluoromethyl, methylthio, methylsulfinyl,methylsulfonyl and aminosulfonyl;

R⁴ and R⁵ are H, OH—(CH₂)₂—, NH₂—C(O)—(CH₂)₂—, CH₃—O—(CH₂)₂—, benzyl,pyridinyl, cyclobutyl, (CH₃)₃—C—, cyclopropyl, CH₃, OH—(CH₂)₃—, or(OH)₂—CH₂—CH—CH₂—;

R⁶ and R⁷ are H, (CH₃)₃—C—, CH₃, benzyl, phenyl, tetrahydropyranyl,cyclohexyl, (CH₃)₂—CH—CH₂—, (CH₃)₂—CH—, or (OH)(CH₃)—CH—;

R⁸, R⁹ and R¹⁰ are H, (CH₃)₃—C—, NH₂—C(O)—, OH—CH₂—, (CH₃CH₂)₂—N—CH₂—,CH₃, (OH) (CH₃)₂—CH—, CH₃—NH—C(O)—CH₂—, cyclopropyl-NH—C(O)CH₂—,NH₂—C(O)—CH₂—NH—C(O)—CH₂—, or COOH—CH₂—; or two of R⁸, R⁹, or R¹⁰ form acyclohexyl, and

R¹¹ and R¹² are H, CH₃, or (CH₃)₃—C—.

In another embodiment the compound or a pharmaceutically acceptable saltthereof, wherein R¹ is selected from the group consisting of

In one embodiment the compound or a pharmaceutically acceptable saltthereof, wherein R¹ is selected from the group consisting of

In one embodiment the compound or a pharmaceutically acceptable saltthereof, wherein R² is selected from the group consisting of

In one embodiment the compound or a pharmaceutically acceptable saltthereof, wherein R² is selected from the group consisting of

In one embodiment the compound selected from the group consisting of

-   N-[1-(aminocarbonyl)cyclohexyl]-3(cyclohexylmethyl)-5-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1R)-1-(aminocarbonyl)-3-methylbutyl]-3-cyclohexylmethyl)-5-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   Nalpha-{[3-(cyclohexylmethyl)-5-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}-L-phenylalaninamide;-   N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-3-(cyclohexylmethyl)-5-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1    S)-1-(aminocarbonyl)-3-methylbutyl]-3-(cyclohexylmethyl)-5-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclohexylmethyl)-7-fluoro-2-oxo-2,3-di    hydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-5-cyano-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide-   N-[(1S)-2-amino-1-cyclohexyl-2-oxoethyl]-3-(cyclohexylmethyl)-5-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S,2R)-1-(aminocarbonyl)-2-hydroxypropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   2-oxo-N-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[1)-2-amino-2-oxo-1-phenylethyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   Nalpha-{[2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}-L-phenylalaninamide;-   N-[(1S)-1-(aminocarbonyl)-3-methylbutyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S,2S)-2-hydroxycyclohexyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[3-(dimethylamino-2,2-dimethylpropyl]-2-oxo-3-tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-2-amino-1-cyclohexyl-2-oxoethyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-methyl-N-{[2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}-L-valine;-   3-hydroxy-N-{[2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}-L-valine;-   N-[(1S)-1-(aminocarbonyl)-2-hydroxy-2-methylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-2-hydroxy-1-(hydroxymethyl)-2-methylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1R)-2-hydroxy-1-(hydroxymethyl)-2-methylpropyl]-2-oxo-3-(tetrahydro-2H-pyran    yl methyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-5-fluoro-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   (3R)-4,4-dimethyl-3-({[2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}amino)pentanoic    acid;-   N-[(1S)-1-aminocarbonyl)-2,2-dimethylpropyl]-3-butyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-(4,4,4-trifluorobutyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-5,6-difluoro-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1R)-1-(2-amino-2-oxoethyl)-2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-(1R)-1-[2-(cyclopropylamino)-2-oxoethyl]-2,2-dimethylpropyl)-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1R)-1-{2-[2-(2-amino-2-oxoethyl)amino]-2-oxoethyl}-2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-{(1S)-1-[(cyclopropylamino)carbonyl]-2,2-dimethylpropyl}-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-{(1S)-1-[(tert-butylamino)carbonyl]-2,2-dimethylpropyl}-2-oxo-3-tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(cyclobutylamino)carbonyl]-2,2-dimethylpropyl)-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   5-fluoro-N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-methyl-N-{[2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazol-1-yl    ]carbonyl}-L-valylglycinamide;-   N-(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl)-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[(4-fluorocyclohex-3-en-1-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide    (diastereomer 1);-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[(4-fluorocyclohex-3-en-1-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide    (diastereomer 2);-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[(4,4-difluorocyclohexyl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-5-bromo-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   5-bromo-3-(cyclohexylmethyl)-N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-{(1R)-2,2-dimethyl-1-[2-(methylamino)-2-oxoethyl]propyl}-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-{(1S)-1-[(cyclopropylamino)carbonyl]-2,2-dimethylpropyl}-5-fluoro-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(2,5-dimethyl-3-furyl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(5-methylisoxazol-3-yl)methyl]-2-oxo-3(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1    carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(2-(dimethylamino)-2-oxoethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[2-(ethylamino)-2-oxoethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(2-cyclopropyl-2-oxoethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(3,3-dimethyl-2-oxobutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-{[(3-hydroxypropyl)amino]carbonyl}-2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(5-amino-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-{[5-methyl-2-(trifluoromethyl)-3-furyl]methyl}-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(5-{[4-(hydroxymethyl)piperidin-1-yl]carbonyl}-1,2,4-oxadiazol-3-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]-2-oxo-3-tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(5-{[(3-methylbutyl)amino]carbonyl}-1,2,4-oxadiazol-3-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(5-isopropyl-1,2,4-oxadiazol-3-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-N-[(1,3,5-trimethyl-1H-pyrazol-4-yl)methyl]-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-(1,3-oxazol-4-ylmethyl)-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(5-ethyl-1,2,4-oxadiazol-3-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(2-ethyl-1,3-thiazol-4-yl)methyl]-2-oxo-3(tetrahydro-2H    pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-(3-furylmethyl)-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(5-{[(3,4-dihydro-1H-isochromen-1-ylmethyl)amino]carbonyl}-1,2,4-oxadiazol-3-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-{[5-(azepan-1-ylcarbonyl)-1,2,4-oxadiazol-3-yl]methyl}-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   2-oxo-N-{[5-({[3-(2-oxopyrrolidin-1-yl)propyl]amino}carbonyl)-1,2,4-oxadiazol-3-yl]methyl}-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   2-oxo-N-({5-[(1,2,3,4-tetrahydronaphthalen-1-ylamino)carbonyl]-1,2,4-oxadiazol-3-yl}methyl)-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-({5-[(dimethylamino)carbonyl]-1,2,4-oxadiazol-3-yl}methyl)-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(5-{[(2-methoxyethyl)amino]carbonyl}-1,2,4-oxadiazol-3-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyrany-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(2,4-dim    ethyl-1,3-thiazol-5-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-({5-[(methylamino)carbonyl]-1,2,4-oxadiazol-3-yl}methyl)-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1-isopropyl-1H-pyrazol-4-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1,3-dimethyl-1H-pyrazol-4-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-di    hydro-1H-benzimidazole-1-carboxamide;-   N-[(2-methyl-1,3-thiazol-4-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(5-{[(trans-4-hydroxycyclohexyl)amino]carbonyl}-1,2,4-oxadiazol-3-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-{([(2S-2,3-dihydroxypropyl]amino}carbonyl)-2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-methyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(5-amino-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropyl]-5-fluoro-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-benzyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-{[2-methyl-4-(trifluoromethyl)-1,3-thiazol-5-yl]methyl}-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[1-(2-methyl-1,3-thiazol-4-yl)ethyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-{[(2R)-5-oxotetrahydrofuran-2-yl]methyl}-2,3-dihydro-1H-benzimidazole-1-carboxamide,-   N-[(1S)-1-(5-amino-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropyl]-2-oxo-3-{[(2R)-5-oxotetrahydrofuran-2-yl]methyl}-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-{[(3-hydroxypropyl)amino]carbonyl}-2,2-dimethylpropyl]-2-oxo-3-{[(2R)-5-oxotetrahydrofuran-2-yl]methyl}-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-2-oxo-3-{[(2R)-5-oxotetrahydrofuran-2-yl]methyl}-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   5-fluoro-N-[(1S)-1-{[(3-hydroxypropyl)amino]carbonyl}-2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   5-fluoro-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(2-fluorobenzyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(5-amino-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropyl]-3-benzyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-benzyl-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-benzyl-N-[(1S)-1-{[(3-hydroxypropyl)amino]carbonyl}-2,2-dimethylpropyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(3-fluorobenzyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(4-fluorobenzyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-pentyl-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-benzyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(2-fluorobenzyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(5-amino-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropyl]-3-benzyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-benzyl-N-[(1S)-1-[(2-hydroxyethyl)amino]carbonyl)-2,2-dimethylpropyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-benzyl-N-[(1S)-1-{[(3-hydroxypropyl)amino]carbonyl}-2,2-dimethylpropyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(4-cyanobenzyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(2-cyanobenzyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3(3-fluorobenzyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-[(1S)-1-aminocarbonyl)-2,2-dimethylpropyl]-3-(4-fluorobenzyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3-(4-fluorobenzyl)-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   3(4-fluorobenzyl)-N-[(1S)-1-{[(3-hydroxypropyl)amino]carbonyl}-2,2-dimethylpropyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;-   N-{[3-(4-fluorobenzyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}-3-methyl-L-valylglycinamide;    and-   N-[(1S)-1-(5-amino-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropyl]-(4-fluorobenzyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;

or a pharmaceutically acceptable salt thereof.

As used herein, the terms “treating”, “treatment”, “treated”, or “totreat,” can be used interchangeably. Treatment includes palliativetreatment, preventive treatment and restorative treatment. Palliativetreatment includes alleviation, elimination of causation of pain and/orinflammation associated with a CB1 mediated disorder. Preventativetreatment means to prevent or to slow the appearance of symptomsassociated with a CB1 mediated disorder. For methods of prevention, thesubject is any subject, and preferably is a subject that is in need ofprevention of a CB1 mediated disorder.

Pharmaceutically acceptable salts of a compound of formula (I) includethe acid addition and base salts (including disalts) thereof.

Suitable acid addition salts are formed from acids which form non-toxicsalts. Examples include the acetate, aspartate, benzoate, besylate,bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate,edisylate, esylate, formate, fumarate, gluceptate, gluconate,glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate,nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate,succinate, tartrate, tosylate and trifluoroacetate salts.

Suitable base salts are formed from bases which form non-toxic salts.Examples include the aluminium, arginine, benzathine, calcium, choline,diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine,potassium, sodium, tromethamine and zinc salts.

For a review on suitable salts, see “Handbook of Pharmaceutical Salts:Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002). A pharmaceutically acceptable salt of acompound of formula (I) may be readily prepared by mixing togethersolutions of the compound of formula (I) and the desired acid or base,as appropriate. The salt may precipitate from solution and be collectedby filtration or may be recovered by evaporation of the solvent. Thedegree of ionisation in the salt may vary from completely ionised toalmost non-ionised.

The compounds useful in the present invention may exist in bothunsolvated and solvated forms. The term ‘solvate’ is used herein todescribe a molecular complex comprising a compound of the invention andone or more pharmaceutically acceptable solvent molecules, for example,ethanol. The term ‘hydrate’ is employed when said solvent is water.

Pharmaceutically acceptable solvates in accordance with the inventioninclude hydrates and solvates wherein the solvent of crystallization maybe isotopically substituted, e.g. D₂O, d₆-acetone, d₆-DMSO

Included within the scope of the invention are complexes such asclathrates, drug-host inclusion complexes wherein, in contrast to theaforementioned solvates, the drug and host are present in stoichiometricor nor-stoichiometric amounts. Also included are complexes of the drugcontaining two or more organic and/or inorganic components which may bein stoichiometric or non-stoichiometric amounts. The resulting complexesmay be ionised, partially ionised, or non-ionised. For a review of suchcomplexes, see J Pharm Sci, 84 (8), 1269-1288 by Haleblian (August1975).

Hereinafter all references to a compound of formula (I) includereferences to salts and complexes thereof and to solvates and complexesof salts thereof.

The term “compound of the invention” or “compounds of the invention”refers to, unless indicated otherwise, a compound of formula (I) ashereinbefore defined, polymorphs, prodrugs, and isomers thereof(including optical, geometric and tautomeric isomers) as hereinafterdefined and isotopically-labeled compounds of formula (I).

Also within the scope of the invention are so-called ‘prodrugs’ of thecompounds of formula (I). Thus certain derivatives of compounds offormula (I) which may have little or no pharmacological activitythemselves can, when administered into or onto the body, be convertedinto compounds of formula (I) having the desired activity, for example,by hydrolytic cleavage. Such derivatives are referred to as ‘prodrugs’.Further Information on the use of prodrugs may be found in ‘Pro-drugs asNovel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and WStella) and ‘Bioreversible Carriers In Drug Design’, Pergamon Press,1987 (ed. E B Roche, American Pharmaceutical Association).

Prodrugs in accordance with the invention can, for example, be producedby replacing appropriate functionalities present in the compounds offormula (I) with certain moieties known to those skilled in the art as‘pro-moieties’ as described, for example, in “Design of Prodrugs” by HBundgaard (Elsevier, 1985). Some examples of prodrugs in accordance withthe invention include:

-   -   (i) where the compound of formula (I) contains an alcohol        functionality (—OH), an ether thereof, for example, replacement        of the hydrogen with (C₁-C₆)alkanoyloxymethyl;    -   (ii) where the compound of formula (I) contains carboxy group,        an ester thereof, for example, replacement of the OH of the        carboxy with C₁-C₈ alkyl; and    -   (ii) where the compound of formula (I) contains a primary or        secondary amino functionality (—NH₂ or —NHR where R≠H), an amide        thereof, for example, replacement of one or both hydrogens with        (C₁-C₁₀)alkanoyl.

Further examples of replacement groups in accordance with the foregoingexamples and examples of other prodrug types may be found in theaforementioned references.

Finally, certain compounds of formula (I) may themselves act as prodrugsof other compounds of formula (I).

Compounds of formula (I) containing one or more asymmetric carbon atomscan exist as two or more stereoisomers. Where the compound contains, forexample, a keto or oxime group or an aromatic moiety, tautomericisomerism (‘tautomerism’) can occur. It follows that a single compoundmay exhibit more than one type of isomerism.

Included within the scope of the present invention are allstereoisomers, geometric Isomers and tautomeric forms of the compoundsof formula (I), including compounds exhibiting more than one type ofisomerism, and mixtures of one or more thereof. Also included are acidaddition or base salts wherein the counterion is optically active, forexample, D-lactate or L-lysine, or racemic, for example, DL-tartrate orDL-arginine.

Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor or resolution of the racemate (or the racemate of a salt orderivative) using, for example, chiral high pressure liquidchromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted witha suitable optically active compound, for example, an alcohol, or, inthe case where the compound of formula (I) contains an acidic or basicmoiety, an acid or base such as tartaric acid or 1-phenylethylamine. Theresulting diastereomeric mixture may be separated by chromatographyand/or fractional crystallization and one or both of thediastereoisomers converted to the corresponding pure enantiomer(s) bymeans well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may beobtained in enantiomerically-enriched form using chromatography,typically HPLC, on an asymmetric resin with a mobile phase consisting ofa hydrocarbon, typically heptane or hexane, containing from 0 to 50%isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine,typically 0.1% diethylamine. Concentration of the eluate affords theenriched mixture.

Stereoisomeric conglomerates may be separated by conventional techniquesknown to those skilled in the art—see, for example, “Stereochemistry ofOrganic Compounds” by E L Eliel (Wiley, New York, 1994).

The present invention includes all pharmaceutically acceptableisotopically-labelled compounds of formula (I) wherein one or more atomsare replaced by atoms having the same atomic number, but an atomic massor mass number different from the atomic mass or mass number usuallyfound in nature.

Examples of isotopes suitable for inclusion in the compounds of theInvention include isotopes of hydrogen, such as ²H and ³H, carbon, suchas ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁸Cl, fluorine, such as ¹⁸F,iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen,such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as³⁵S.

Certain isotopically-labelled compounds of formula (I), for example,those incorporating a radioactive isotope, are useful in drug and/orsubstrate tissue distribution studies. The radioactive isotopes tritium,i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for thispurpose in view of their ease of incorporation and ready means ofdetection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy.

Isotopically-labeled compounds of formula (I) can generally be preparedby conventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examples andPreparations using an appropriate isotopically-labeled reagents in placeof the non-labeled reagent previously employed.

All of the compounds of the formula (I) can be prepared by theprocedures described in the general methods presented below or by thespecific methods described in the Examples section and the Preparationssection, or by routine modifications thereof. The present invention alsoencompasses any one or more of these processes for preparing thecompounds of formula (I), in addition to any novel intermediates usedtherein.

General Synthesis

The compounds of the present invention may be prepared by a variety ofprocesses well known for the preparation of compounds of this type, forexample as shown in the following Methods A to D.

The following Method A illustrates the preparation of compounds offormula (I). Methods B through D illustrate the preparation of variousintermediates.

Unless otherwise indicated, R¹, R², R³, A and B in the following Methodsare as defined above. The term “protecting group”, as used hereinafter,means a hydroxy, carboxy or amino-protecting group which is selectedfrom typical hydroxy, carboxy or amino-protecting groups described inProtective Groups in Organic Synthesis edited by T. W. Greene et al.(John Wiley & Sons, 1999). All starting materials in the followinggeneral syntheses may be commercially available or obtained byconventional methods known to those skilled in the art, such asMeth-Cohn, O.; Smith, D. I. J.C.S., Perkin Trans. 1, 1982, 261; Vernin,G.; Domlog, H.; Siv, C.; Metzger, J. J. Heterocyclic Chem. 1981, 18, 85;Emily, M. S. et al. Tetrahedron 2001, 57, 5303-5320; Kubo, K. et al. J.Med. Chem. 1993, 36, 1772-1784; Israel, M.; Jones, L. C. J. HeterocyclicChem. 1971, 8, 797; Sebok, P.; Levai, A.; Timar, T. Heterocyclic Commun.1998, 4, 547-552.); and the disclosures of which are incorporated hereinby references.

Method A

This illustrates the preparation of compounds of formula (I).

Step A1

In this step, the desired compound of formula (I) of the presentinvention is prepared by carbonylation of the compound of formula (II)with the compound of formula (III). The compound of formula (II) iscommercially available or can be prepared according to the Methods B andC set forth below. The compound of formula (III) is commerciallyavailable.

The reaction is normally and preferably effected in the presence ofsolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor the reagents involved and that it can dissolve reagents, at least tosome extent. Examples of suitable solvents include, but are not limitedto: halogenated hydrocarbons, such as dichloromethane, chloroform,carbon tetrachloride and 1,2-dichloroethane; aromatic hydrocarbons, suchas benzene, toluene and nitrobenzene; ethers, such as diethyl ether,diisopropyl ether, tetrahydrofuran and dioxane; and amides, such asN,N-dimethylformamide and N,N-dimethylacetamide. Of these solvents,dichloromethane is preferred.

There is likewise no particular restriction on the nature of thecarbonylating agents used, and any carbonylating agent commonly used inreactions of this type may equally be used here. Examples of suchcarbonylating agents include, but are not limited to: an imidazolederivative such as N,N′-carbonyldiimidazole (CDI); a chloroformate suchas trichloromethyl chloroformate and 4-nitrophenyl chloroformate; urea;and triphosgene. Of these, 4-nitrophenyl chloroformate is preferred.

The reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Thepreferred reaction temperature will depend upon such factors as thenature of the solvent, and the starting materials. However, in general,it is convenient to carry out the reaction at a temperature of fromabout 0 degrees Celsius to about 100 degrees Celsius. The time requiredfor the reaction may also vary widely, depending on many factors,notably the reaction temperature and the nature of the startingmaterials and solvent employed. However, provided that the reaction iseffected under the preferred conditions outlined above, a period of fromabout 5 minutes to about 24 hours will usually suffice.

Method B

This illustrates the preparation of compounds of formula (II).

In Reaction Scheme B, R⁴ is an amide-protecting group; X is a leavinggroup.

The term “amide-protecting group”, as used herein, signifies aprotecting group capable of being cleaved by chemical means, such ashydrogenolysis, hydrolysis, electrolysis or photolysis and suchamide-protecting groups are described in Protective Groups in OrganicSynthesis edited by T. W. Greene et al., (John Wiley & Sons, 1999).Typical amide-protecting groups include, but are not limited to, allyl,isopropenyl, t-butyl, methoxymethyl, benzyloxy and t-butyldimethylsilyl.Of these groups, isopropenyl is preferred.

The term “leaving group”, as used herein, signifies a group capable ofbeing substituted by nucleophilic groups, such as a hydroxy group,amines or carboanions and examples of such leaving groups includehalogen atoms, a alkylsulfonyl group and a phenylsulfonyl group. Ofthese, a bromine atom, a chlorine atom and a methylsulfonyl group arepreferred.

Step B1

In this step, the compound of formula (II) is prepared by thenucleophilic substitution (B1-a) with the compound of formula (V)followed by deprotection (B1-b). The compound of formula (IV) iscommercially available or can be prepared according to the methodsdescribed in Israel, M.; Jones, L. C. J. Heterocyclic Chem. 1971, 8,797. The compound of formula (V) is commercially available.

(B1-a) Nucleophilic Substitution

The reaction is normally and preferably effected in the presence ofsolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor the reagents involved and that it can dissolve reagents, at least tosome extent. Examples of suitable solvents include: ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; amides,such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide andhexamethylphosphoric triamide; nitrites, such as acetonitrile andbenzonitrile; and sulfoxides, such as dimethyl sulfoxide and sulfolane.Of these solvents, N,N-dimethylformamide is preferred.

The reaction is carried out in the presence of a base. There is likewiseno particular restriction on the nature of the bases used, and any basecommonly used in reactions of this type may equally be used here.Examples of such bases include: alkali metal hydrides, such as lithiumhydride, sodium hydride and potassium hydride; and alkali metal amides,such as lithium amide, sodium amide, potassium amide, lithiumdiisopropyl amide, potassium diisopropyl amide, sodium diisopropylamide, lithium bis(trimethylsilyl)amide and potassiumbis(trimethylsilyl)amide. Of these, sodium hydride is preferred.

The reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Thepreferred reaction temperature will depend upon such factors as thenature of the solvent, and the starting materials. However, in general,it is convenient to carry out the reaction at a temperature of fromabout −20 degrees Celsius to about 50 degrees Celsius. The time requiredfor the reaction may also vary widely, depending on many factors,notably the reaction temperature and the nature of the startingmaterials and solvent employed. However, provided that the reaction iseffected under the preferred conditions outlined above, a period of fromabout 30 minutes to about 24 hours, will usually suffice.

(B1-b) Deprotection

The deprotection method is described in detail by T. W. Greene et al.[Protective Groups in Organic Synthesis, 494-653, (1999)], thedisclosures of which are incorporated herein by reference. The followingexemplifies a typical method involving the protecting group isisopropenyl.

The reaction is normally and preferably effected in the presence ofsolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor the reagents involved and that it can dissolve reagents, at least tosome extent. Examples of suitable solvents include, but are not limitedto: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuranand dioxane; water; and alcohols, such as methanol, ethanol, propanol,2-propanol and butanol. Of these solvents, water or alcohols arepreferred.

The reaction is carried out in the presence of excess amount of an acid.There is likewise no particular restriction on the nature of the acidsused, and any acid commonly used in reactions of this type may equallybe used here. Examples of such acids include, but are not limited to:acids, such as hydrochloric acid, sulfuric acid or trifluoroacetic acid.Of these, hydrochloric acid is preferred.

The reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Thepreferred reaction temperature will depend upon such factors as thenature of the solvent, and the starting materials. However, in general,it is convenient to carry out the reaction at a temperature of fromabout 25 degrees Celsius to about 120 degrees Celsius. The time requiredfor the reaction may also vary widely, depending on many factors,notably the reaction temperature and the nature of the startingmaterials and solvent employed. However, provided that the reaction iseffected under the preferred conditions outlined above, a period of fromabout 15 minutes to about 12 hours, will usually suffice.

Method C

This illustrates the preparation of compounds of formula (II).

In Reaction Scheme C, X is as defined above.

Step C1

In this step, the compound of formula (VII) is prepared by thenucleophilic substitution of the compound of formula (VI) with thecompound of formula (V). The compound of formula (VI) is commerciallyavailable or can be prepared according to the methods described in Kubo,K. et al. J. Med. Chem. 1993, 36, 1772-1784. The compound of formula (V)is commercially available. The reaction may be carried out under thesame conditions as described in Step B1-a of Method B.

Step C2

In this step, the compound of formula (VIII) is prepared by thereduction of the nitro group.

The reaction is normally and preferably effected in the presence ofsolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor the reagents involved and that it can dissolve reagents, at least tosome extent. Examples of suitable solvents include: ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aromatichydrocarbons, such as benzene and toluene; alcohols, such as methanol,ethanol, propanol, 2-propanol and butanol; and esters, such as ethylacetate. Of these solvents, tetrahydrofuran is preferred.

The reaction is carried out in the presence of a reducing agent. Thereis likewise no particular restriction on the nature of the reducingagents used, and any reducing agent commonly used in reactions of thistype may equally be used here. Examples of such reducing agents include:hydride compounds such as lithium aluminum hydride, sodium borohydrideand diisobutyl aluminum hydride; combinations of hydrogen gas and acatalyst such as palladium-carbon, platinum and Raney nickel; and acombination of metals, such as zinc and iron, and acids, such ashydrochloric acid, acetic acid and acetic acid-ammonium chloridecomplex. Of these, lithium aluminum hydride is preferred.

The reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Thepreferred reaction temperature will depend upon such factors as thenature of the solvent, and the starting materials. However, in general,it is convenient to carry out the reaction at a temperature of fromabout 25 degrees Celsius to about 120 degrees Celsius. The time requiredfor the reaction may also vary widely, depending on many factors,notably the reaction temperature and the nature of the startingmaterials and solvent employed. However, provided that the reaction iseffected under the preferred conditions outlined above, a period of fromabout 15 minutes to about 24 hours will usually suffice.

Step C3

In this step, the compound of formula (II) is prepared by the formationof the cyclic urea of the compound of formula (VIII).

The reaction is normally and preferably effected in the presence ofsolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor the reagents involved and that it can dissolve reagents, at least tosome extent. Examples of suitable solvents include, but are not limitedto: halogenated hydrocarbons, such as dichloromethane, chloroform,carbon tetrachloride and 1,2-dichloroethane; aromatic hydrocarbons, suchas benzene, toluene and nitrobenzene; ethers, such as diethyl ether,diisopropyl ether, tetrahydrofuran and dioxane; and amides, such asN,N-dimethylformamide and N,N-dimethylacetamide. Of these solvents,tetrahydrofuran is preferred.

There is likewise no particular restriction on the nature of thecarbonylating agents used, and any carbonylating agent commonly used inreactions of this type may equally be used here. Examples of suchcarbonylating agents include, but are not limited to: an imidazolederivative such as N,N′-carbonyldiimidazole (CDI); a chloroformate suchas trichloromethyl chloroformate and 4-nitrophenyl chloroformate; urea;and triphosgene. Of these, CDI or urea is preferred.

The reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Thepreferred reaction temperature will depend upon such factors as thenature of the solvent, and the starting materials. However, in general,it is convenient to carry out the reaction at a temperature of fromabout 0 degrees Celsius to about 100 degrees Celsius. The time requiredfor the reaction may also vary widely, depending on many factors,notably the reaction temperature and the nature of the startingmaterials and solvent employed. However, provided that the reaction iseffected under the preferred conditions outlined above, a period of fromabout 30 minutes to about 12 hours will usually suffice.

Method D

This illustrates the preparation of compounds of formula (II).

In Reaction Scheme-C, Y is a chlorine atom or fluorine atom.

Step D1

In this step, the compound of formula (VII) is prepared by thenucleophilic substitution of the compound of formula (IX) with thecompound of formula (X). The compound of formula (IX) is commerciallyavailable or can be prepared according to the methods described inOrjales, A. et al. J. Med. Chem. 1999, 42, 2870-2880. The compound offormula (X) is commercially available.

The reaction is normally and preferably effected in the presence ofsolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor the reagents involved and that it can dissolve reagents, at least tosome extent. Examples of suitable solvents include, but are not limitedto: halogenated hydrocarbons, such as dichloromethane, chloroform,carbon tetrachloride and 1,2-dichloroethane; aromatic hydrocarbons, suchas benzene, toluene and nitrobenzene; ethers, such as diethyl ether,diisopropyl ether, tetrahydrofuran and dioxane; alcohols, such asmethanol, ethanol, propanol, 2-propanol and butanol; and amides, such asN,N-dimethylformamide and N,N-dimethylacetamide. Of these solvents,tetrahydrofuran is preferred.

The reaction is carried out in the presence of a base. There is likewiseno particular restriction on the nature of the bases used, and any basecommonly used in reactions of this type may equally be used here.Examples of such bases include: alkali metal alkoxides, such as sodiummethoxide, sodium ethoxide and potassium t-butoxide; alkali metalcarbonates, such as lithium carbonate, sodium carbonate and potassiumcarbonate; amines, such as N-methylmorpholine, triethylamine,tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine,N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline,4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine,quinoline, N,N-dimethylaniline, N,N-diethylaniline,1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane(DABCO) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); and alkali metalhydrogencarbonates, such as lithium hydrogencarbonate, hydrogensodiumcarbonate and potassium hydrogencarbonate. Of these, potassium carbonateis preferred.

The reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Thepreferred reaction temperature will depend upon such factors as thenature of the solvent, and the starting materials. However, in general,it is convenient to carry out the reaction at a temperature of fromabout −20 degrees Celsius to about 120 degrees Celsius. The timerequired for the reaction may also vary widely, depending on manyfactors, notably the reaction temperature and the nature of the startingmaterials and solvent employed. However, provided that the reaction iseffected under the preferred conditions outlined above, a period of fromabout 1 hour to about 36 hours will usually suffice. In this reaction,microwave can be employed to accelerate the reaction. In the case ofemploying microwave, the reaction at a temperature may be from about 50degrees Celsius to about 220 degrees Celsius and the reaction time fromabout 5 minutes to about 6 hours will usually suffice.

Steps D2 and D3

The reactions may be carried out under the same conditions as describedin Steps C2 and C3.

The compounds of formula (I), and the intermediates above-mentionedpreparation methods can be isolated and purified by conventionalprocedures, such as distillation, recrystallization or chromatographicpurification.

Compounds of the invention intended for pharmaceutical use may beadministered as crystalline or amorphous products. They may be obtained,for example, as solid plugs, powders, or films by methods such asprecipitation, crystallization, freeze drying, spray drying, orevaporative drying. Microwave or radio frequency drying may be used forthis purpose.

They may be administered alone or in combination with one or more othercompounds of the invention or in combination with one or more otherdrugs (or as any combination thereof). Generally, they will beadministered as a pharmaceutical composition or formulation inassociation with one or more pharmaceutically acceptable carriers orexcipients. The term “carrier” or “excipient” is used herein to describeany ingredient other than the compound(s) of the invention. The choiceof carrier or excipient will to a large extent depend on factors such asthe particular mode of administration, the effect of the excipient onsolubility and stability, and the nature of the dosage form.

Pharmaceutical compositions suitable for the delivery of compounds ofthe present invention and methods for their preparation will be readilyapparent to those skilled in the art. Such compositions and methods fortheir preparation may be found, for example, in ‘Remington'sPharmaceutical Sciences’, 19th Edition (Mack Publishing Company, 1995).

Oral Administration

The compounds of the invention may be administered orally. Oraladministration may involve swallowing, so that the compound enters thegastrointestinal tract, or buccal or sublingual administration may beemployed by which the compound enters the blood stream directly from themouth.

Formulations suitable for oral administration include solid formulationssuch as, for example, tablets, capsules containing particulates,liquids, or powders, lozenges (including liquid-filled), chews, multi-and nano-particulates, gels, solid solution, liposome, films (includingmuco-adhesive), ovules, sprays and liquid formulations.

Liquid formulations include, for example, suspensions, solutions, syrupsand elixirs. Such formulations may be employed as fillers in soft orhard capsules and typically comprise a carrier, for example, water,ethanol, polyethylene glycol, propylene glycol, methylcellulose, or asuitable oil, and one or more emulsifying agents and/or suspendingagents. Liquid formulations may also be prepared by the reconstitutionof a solid, for example, from a sachet.

The compounds of the invention may also be used In fast-dissolving,fast-disintegrating dosage forms such as those described in ExpertOpinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen(2001).

For tablet dosage forms, depending on dose, the drug may make up fromabout 1 wt % to about 80 wt % of the dosage form, more typically fromabout 5 wt % to about 60 wt % of the dosage form. In addition to thedrug, tablets generally contain a disintegrant. Examples ofdisintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethyl cellulose, croscarmellose sodium,crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystallinecellulose, lower alkyl-substituted hydroxypropyl cellulose, starch,pregelatinised starch and sodium alginate. Generally, the disintegrantwill comprise from about 1 wt % to about 25 wt %, preferably from about5 wt % to about 20 wt % of the dosage form.

Binders are generally used to impart cohesive qualities to a tabletformulation. Suitable binders include microcrystalline cellulose,gelatin, sugars, polyethylene glycol, natural and synthetic gums,polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose andhydroxypropyl methylcellulose. Tablets may also contain diluents, suchas lactose (monohydrate, spray-dried monohydrate, anhydrous and thelike), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystallinecellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally comprise surface active agents, such assodium lauryl sulfate and polysorbate 80, and glidants such as silicondioxide and talc. When present, surface active agents may comprise fromabout 0.2 wt % to about 5 wt % of the tablet, and glidants may comprisefrom about 0.2 wt % to about 1 wt % of the tablet.

Tablets also generally contain lubricants such as magnesium stearate,calcium stearate, zinc stearate, sodium stearyl fumarate, and mixturesof magnesium stearate with sodium lauryl sulphate. Lubricants generallycomprise from about 0.25 wt % to about 10 wt %, preferably from about0.5 wt % to about 3 wt % of the tablet.

Other possible ingredients include anti-oxidants, colourants, flavouringagents, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80% drug, from about 10 wt % toabout 90 wt % binder, from about 0 wt % to about 85 wt % diluent, fromabout 2 wt % to about 10 wt % disintegrant, and from about 0.25 wt % toabout 10 wt % lubricant.

Tablet blends may be compressed directly or by roller to form tablets.Tablet blends or portions of blends may alternatively be wet-, dry-, ormelt-granulated, melt congealed, or extruded before tabletting. Thefinal formulation may comprise one or more layers and may be coated oruncoated; it may even be encapsulated.

The formulation of tablets is discussed in “Pharmaceutical Dosage Forms:Tablets, Vol. 1”, by H. Lieberman and L. Lachman, Marcel Dekker, N.Y.,N.Y., 1980 (ISBN 0-8247-6918-X).

Solid formulations for oral administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

Suitable modified release formulations for the purposes of the inventionare described in U.S. Pat. No. 6,106,864. Details of other suitablerelease technologies such as high energy dispersions and osmotic andcoated particles are to be found in Verma et al, PharmaceuticalTechnology On-line, 25(2), 1-14 (2001). The use of chewing gum toachieve controlled release is described in WO 00/35298.

Parenteral Administration

The compounds of the invention may also be administered directly intothe blood stream, into muscle, or into an internal organ. Suitable meansfor parenteral administration include intravenous, intraarterial,intraperitoneal, intrathecal, intraventricular, intraurethral,intrasternal, intracranial, intramuscular and subcutaneous. Suitabledevices for parenteral administration include needle (includingmicroneedle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which maycontain excipients such as salts, carbohydrates and buffering agents(preferably to a pH of from about 3 to about 9), but, for someapplications, they may be more suitably formulated as a sterilenon-aqueous solution or as a dried form to be used in conjunction with asuitable vehicle such as sterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, forexample, by lyophilisation, may readily be accomplished using standardpharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of formula (I) used in the preparation ofparenteral solutions may be increased by the use of appropriateformulation techniques, such as the incorporation ofsolubility-enhancing agents.

Formulations for parenteral administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease. Thus compounds of the invention may be formulated as a solid,semi-solid, or thixotropic liquid for administration as an implanteddepot providing modified release of the active compound. Examples ofsuch formulations include drug-coated stents and PGLA microspheres.

Topical Administration

The compounds of the invention may also be administered topically to theskin or mucosa, that is, dermally or transdermally. Typical formulationsfor this purpose include gels, hydrogels, lotions, solutions, creams,ointments, dusting powders, dressings, foams, films, skin patches,wafers, implants, sponges, fibres, bandages and microemulsions.Liposomes may also be used. Typical carriers include alcohol, water,mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethyleneglycol and propylene glycol. Penetration enhancers may beincorporated—see, for example, J Pharm Sci, 88 (10), 955958 by Finninand Morgan (October 1999).

Other means of topical administration include delivery byelectroporation, iontophoresis, phonophoresis, sonophoresis andmicroneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection.

Formulations for topical administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

Inhaled/Intranasal Administration

The compounds of the invention can also be administered intranasally orby inhalation, typically in the form of a dry powder (either alone, as amixture, for example, in a dry blend with lactose, or as a mixedcomponent particle, for example, mixed with phospholipids, such asphosphatidylcholine) from a dry powder inhaler or as an aerosol sprayfrom a pressurized container, pump, spray, atomiser (preferably anatomiser using electrohydrodynamics to produce a fine mist), ornebuliser, with or without the use of a suitable propellant, such as1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. Forintranasal use, the powder may comprise a bioadhesive agent, forexample, chitosan or cyclodextrin.

The pressurized container, pump, spray, atomizer, or nebuliser containsa solution or suspension of the compound(s) of the invention comprising,for example, ethanol, aqueous ethanol, or a suitable alternative agentfor dispersing, solubilising, or extending release of the active, apropellant(s) as solvent and an optional surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug productis micronised to a size suitable for delivery by inhalation (typicallyless than 5 microns). This may be achieved by any appropriatecomminuting method, such as spiral jet milling, fluid bed Jet milling,supercritical fluid processing to form nanoparticles, high pressurehomogenization, or spray drying.

Capsules (made, for example, from gelatin or HPMC), blisters andcartridges for use in an inhaler or insufflator may be formulated tocontain a powder mix of the compound of the invention, a suitable powderbase such as lactose or starch and a performance modifier such asl-leucine, mannitol, or magnesium stearate. The lactose may be anhydrousor in the form of the monohydrate, preferably the latter. Other suitableexcipients include dextran, glucose, maltose, sorbitol, xylitol,fructose, sucrose and trehalose.

A suitable solution formulation for use in an atomiser usingelectrohydrodynamics to produce a fine mist may contain from about 1 μgto about 20 mg of the compound of the invention per actuation and theactuation volume may vary from about 1 μl to about 100 μl. A typicalformulation may comprise a compound of formula (I), propylene glycol,sterile water, ethanol and sodium chloride. Alternative solvents whichmay be used instead of propylene glycol include glycerol andpolyethylene glycol.

Suitable flavours, such as menthol and levomenthol, or sweeteners, suchas saccharin or saccharin sodium, may be added to those formulations ofthe invention intended for inhaled/intranasal administration.Formulations for inhaled/intranasal administration may be formulated tobe immediate and/or modified release using, for example,poly(DL-lactic-coglycolic acid (PGLA). Modified release formulationsinclude delayed-, sustained-, pulsed-, controlled-, targeted andprogrammed release.

In the case of dry powder inhalers and aerosols, the dosage unit isdetermined by means of a valve which delivers a metered amount. Units inaccordance with the invention are typically arranged to administer ametered dose or “puff” containing from about 1 to about 100 μg of thecompound of formula (I). The overall daily dose will typically be in therange about 50 μg to about 20 mg which may be administered in a singledose or, more usually, as divided doses throughout the day.

Rectal/Intravaginal Administration

The compounds of the invention may be administered rectally orvaginally, for example, in the form of a suppository, pessary, or enema.Cocoa butter is a traditional suppository base, but various alternativesmay be used as appropriate.

Formulations for rectal/vaginal administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

Ocular/Aural Administration

The compounds of the invention may also be administered directly to theeye or ear, typically in the form of drops of a micronised suspension orsolution in isotonic, pH-adjusted, sterile saline. Other formulationssuitable for ocular and aural administration include ointments,biodegradable (e.g. absorbable gel sponges, collagen) andnon-biodegradable (e.g. silicone) implants, wafers, lenses andparticulate or vesicular systems, such as niosomes or liposomes. Apolymer such as crossed-linked polyacrylic acid, polyvinylalcohol,hyaluronic acid, a cellulosic polymer, for example,hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum,may be incorporated together with a preservative, such as benzalkoniumchloride. Such formulations may also be delivered by iontophoresis.

Formulations for ocular/aural administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted, or programmedrelease.

Other Technologies

The compounds of the invention may be combined with solublemacromolecular entitles, such as cyclodextrin and suitable derivativesthereof or polyethylene glycol-containing polymers, in order to improvetheir solubility, dissolution rate, taste-masking, bioavailabilityand/or stability for use in any of the aforementioned modes ofadministration.

Drug-cyclodextrin complexes, for example, are found to be generallyuseful for most dosage forms and administration routes. Both inclusionand non-inclusion complexes may be used. As an alternative to directcomplexation with the drug, the cyclodextrin may be used as an auxiliaryadditive, i.e. as a carrier, diluent, or solubiliser. Most commonly usedfor these purposes are alpha-, beta- and gamma-cyclodextrins, examplesof which may be found in. WO 91/11172, WO 94/02518 and WO 98/55148.

Kit-of-Parts

Inasmuch as it may be desirable to administer a combination of activecompounds, for example, for the purpose of treating a particular diseaseor condition, it is within the scope of the present invention that twoor more pharmaceutical compositions, at least one of which contains acompound in accordance with the invention, may conveniently be combinedin the form of a kit suitable for coadministration of the compositions.

Thus the kit of the invention comprises two or more separatepharmaceutical compositions, at least one of which contains a compoundof formula (I) in accordance with the invention, and means forseparately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is the familiarblister pack used for the packaging of tablets, capsules and the like.

The kit of the invention is particularly suitable for administeringdifferent dosage forms, for example, oral and parenteral, foradministering the separate compositions at different dosage intervals,or for titrating the separate compositions against one another. Toassist compliance, the kit typically comprises directions foradministration and may be provided with a so-called memory aid.

Dosage

For administration to human patients, the total daily dose of thecompounds of the invention is typically in the range of about 0.05 mg toabout 100 mg depending, of course, on the mode of administration,preferred in the range of about 0.1 mg to about 50 mg and more preferredin the range of about 0.5 mg to about 20 mg. For example, oraladministration may require a total daily dose of from about 1 mg toabout 20 mg, while an intravenous dose may only require from about 0.5mg to about 10 mg. The total daily dose may be administered in single ordivided doses.

These dosages are based on an average human subject having a weight ofabout 65 kg to about 70 kg. The physician will readily be able todetermine doses for subjects whose weight falls outside this range, suchas infants and the elderly.

Combination

As discussed above, a compound of the invention exhibits CB1 receptorbinding activity. A CB1 ligand of the present invention may be usefullycombined with another pharmacologically active compound, or with two ormore other pharmacologically active compounds, particularly in thetreatment of the cancer, inflammatory diseases, immunomodulatorydiseases and gastrointestinal disorder. For example, a CB1 ligands,particularly a compound of the formula (I), or a pharmaceuticallyacceptable salt thereof, as defined above, may be administeredsimultaneously, sequentially or separately in combination with one ormore agents selected from:

-   (i) 5-HT₃ antagonists, e.g. dolasetron, palonosetron, alosetron,    azasetron and ramosetron, mitrazapine, granisetron, tropisetron,    E-3620, ondansetron and indisetron;-   (ii) 5-HT₄ agonists, e.g. tegaserod, mosapride, cinitapride and    oxtriptane;-   (iii) opioid analgesics, e.g. morphine, heroin, hydromorphone,    oxymorphone, levorphanol, levallorphan, methadone, meperidine,    fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone,    propoxyphene, nalmefene, nalorphine, naloxone, naltrexone,    buprenorphine, butorphanol, nalbuphine Modulon® (trimebutine    malate), Imodium® (loperamide) and pentazocine;-   (iv) tricyclic antidepressants, e.g. imipramine, amitriptyline,    clomipramine, amoxapine and lofepramine;-   (v) somatostatin analogues, e.g. octreotide, AN238 and PTR-3173;-   (vi) anticholinergics, e.g. dicyclomine and hyoscyamine, ipratroplum    bromide, ipratroplum, tiotropium bromide;-   (vii) laxatives, e.g. Trifyba®, Fybogel®, Konsyl®, Isoget®,    Regulan®, Celevac® and Normacol®;-   (viii) fiber products, e.g. Metamucil®;-   (ix) antispasmodics, e.g.: mebeverine;-   (x) dopamine antagonists, e.g. metoclopramide, domperidone and    levosulpiride;-   (xi) cholinergics, e.g. neostigmine, pilocarpine, carbachol-   (xii) calcium channel blockers, e.g. aranidipine, lacidipine,    falodipine, azelnidipine, clinidipine, lomerizine, diltiazem,    gallopamil, efonidipine, nisoldipine, amlodipine, lercanidipine,    bevantolol, nicardipine, isradipine, benidipine, verapamil,    nitrendipine, barnidipine, propafenone, manidipine, bepridil,    nifedipine, nilvadipine, nimodipine and fasudil;-   (xiii) Cl Channel activator: e.g. lubiprostone;-   (xiv) selective serotonin reuptake inhibitors, e.g. sertraline,    escitalopram, fluoxetine, nefazodone, fluvoxamine, citalopram,    milnacipran, paroxetine, venlafaxine, tramadol, sibutramine,    duloxetine, desvenlafaxine and depoxetine;-   (xv) GABA agonists, e.g. gabapentin, topiramate, cinolazepam,    clonazepam, progabide, brotizolam, zopiclone, pregabalin and    eszopiclone;-   (xvi) tachykinin (NK) antagonists, particularly NK-3, NK-2 and NK-1    antagonists, e.g.: nepadutant, saredutant, talnetant,    (αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthridine-6-13-dione    (TAK-637),    5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one    (MK-869), lanepitant, dapitant and    3-[[2-methoxy-5-(trifluoromethoxy)phenyl]methylamino]-2-phenyl-piperidine    (2S,3S).-   (xvii). α2 agonists, e.g. clonidine, medetomidine, lofexidine,    moxonidine, tizanidine, guanfacine, guanabenz, talipexole and    dexmedetomidine;-   (xviii) benzodiazepine agonists, e.g. diazepam, zaleplon, zolpidem,    haloxazolam, clonazepam, prazepam, quazepam, flutazolam, triazolam,    lormetazepam, midazolam, tofisopam, clobazam, flunitrazepam and    flutoprazepam;-   (xix) prostaglandin analogues, e.g. Prostaglandin, misoprostol,    treprostinil, esoprostenol, latanoprost, iloprost, beraprost,    enprostil, ibudilast and ozagrel;-   (xx) histamine H₃ agonists, e.g. R-alpha-methylhistamine and BP-294;-   (xxi) anti-gastric agents, e.g. Anti-gastrin vaccine, itriglumide    and Z-360;-   (xxii) disease modifying anti-rheumatic drugs (DMARDS), e.g.    methotrexate, leflunomide, penicillamine aurothiopropanol sulfonate,    sulfasalazine, mesalamine, olsalazine, balsalazide, Hylan G-F 20,    glucosamine, chondroitin sulfate, hydroxychloroquine and diacerein.-   (xxiii) Tumor Necrosis Factor-Alpha (TNF-α) modulators, e.g.    etanercept, infliximab, adalimumab, CDP-870, pegsunercept,    ISIS-104838, RDP-58 and thalidomide;-   (xxiv) interleukin-based therapies, e.g. anakinra, atlizumabi    RGN-303, denileukindiftitox, ilodecakin, oprelvekin and mepolizumab;-   (xxv) nonsteroidal antiinflammatory drugs (NSAIDs), e.g. piroxicam,    naproxen, indomethacin, ibuprofen, diclofenac, ketorolac,    flurbiprofen, aspirin, diflusinal, etodolac, fenbufen, fenoprofen,    flufenisal, ketoprofen, meclofenamic acid, mefenamic acid,    nabumetone, oxaprozin, phenylbutazone, sulindac, tolmetin and    zomepirac;-   (xxvi) selective COX-2 inhibitors, e.g. celecoxib, rofecoxib,    valdecoxib, etoricoxib, lumiracoxib and LAS-34475;-   (xxvii) Centrally Acting Analgesics, e.g. tramadol and oxymorphone    ER;-   (xxviii) immunosupressives, e.g. cyclosporine, tacrolimus,    rapamycin, azathioprine and mycophenolate mofetil;-   (xxix) Multiple Sclerosis (MS) treatments, e.g. interferonβ-1b,    interferonβ-1α, glatiramer gcetate, mitoxantrone, cyclophosphamide,    MBP-8298, AG-284, tiplimotide, BX-471, E-2007, recombinant glial    growth factor-2 and natalizumab;-   (xxx) Monoclonal Antibodies, e.g. natalizumab, daclizumab,    alemtuzumab, omalizumab, TNX-100 and SGN-40;-   (xxxi) insulin secretagogues, e.g. glyburide, glipizide, repaglinide    and glimiperide;-   (xxxii) biguanides, e.g. metformin;-   (xxxiii) alpha-glucosidase inhibitors, e.g. acarbose, voglibose and    miglitol;-   (xxxiv) PPAR γ agonists, e.g. ploglitazone and rosiglitazone;-   (xxxv) antibiotics, e.g. sulfacetamide, erythromycin, gentamicin,    tobramycin, ciprofloxacin and ofloxacin-   (xxxvi) cell adhesion molecule inhibitors, e.g. alicaforsen, MLN-02,    alefacept, efalizumab, R-411 and IVL-745;-   (xxxvii) anti-allergy drugs, e.g. levocabastine, olopatadine,    cromolyn, iodoxamide, pheniramine, ketotifen, mizolastine and    epinastine;-   (xxxviii) opthalmologic anti-virals, e.g. adenine arabinoside and    idoxuridine;-   (xxxix) glaucoma treatments, e.g. timolol, metipranolol, carteolol,    betaxolol, levobunolol, brimonidine, iopidine, dorzolamide,    epinephrine and dipivefrin;-   (xl) alkylating anti-tumor agents, e.g. busulfan, carboplatin,    chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide,    mechlorethamine, melphalan, procarbazine, thiotepa, and uracil    mustard;-   (xli) nitrosoureas, e.g. carmustine, lumustine and streptozocin;-   (xlii) antimetabolites, e.g. 5-fluorouracil, 6-mercaptopurine,    capecitabine, cytosine arabinoside, floxuridine, fludarabine,    gemcitabine, rhethotrexate, thioguanine and azathioprine;-   (xliii) antitumor biotics, e.g. dactinomycin, daunorubicin,    doxorubicin, idarubicin, mitomycin-C, and mitoxantrone;-   (xliv) anti-microtuble agents, e.g. vinblastine, vincristine,    vindesine, vinorelbine, paclitaxel and docetaxel;-   (xlv) vitamine derivatives, e.g., calcipotriol and tacalcitol;-   (xivi) leukotriene antagonists, e.g. montelukast, zafirlukast and    praniukast;-   (xlvii) β2 Agonists, e.g. albuterol, levalbuterol, salmeterol,    formrotero and arformoterol;-   (xlviii) corticosteroids, e.g. prednisone, ciclesonide, budesonide,    fluticasone methylprednisolone, hydrocortisone and BP-1011;-   (xlix) methylxanthines, e.g. theophylline, aminophylline and    doxofylilne; and-   (l) asthma and/or COPD treatments, e.g. roflumilast, tiotropium,    israpafant, N-acetylcysteine and α1-antitrypsin.-   (li) a vanilloid receptor agonist (e.g. resinferatoxin) or    antagonist (e.g. capsazepine);-   (lii) an alpha-2-delta ligand such as gabapentin, pregabalin,    3-methylgabapentin,    (1α,3α,5α)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid,    (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid,    (3S,5R)-3-amino-5-methyl-heptanoic acid,    (3S,5R)-3-amino-5-methyl-octanoic acid,    (2S,4S)-4(3-chlorophenoxy)proline,    (2S,4S)-4-(3-fluorobenzyl)-proline,    [(1R,5R,6S)-6-aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid,    3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one,    C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine,    (3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)acetic acid,    (3S,5R)-3-aminomethyl-5-methyl-octanoic acid,    (3S,5R)-3-amino-5-methyl-nonanoic acid,    (3S,5R)-3-amino-5-methyl-octanoic acid,    (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and    (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid; and-   (liii) a prostaglandin E₂ subtype 4 (EP4) antagonist such as    N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide    or    4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic    acid.

Biological Evaluation Method for Assessing Biological Activities:

The Human CB1 receptor binding affinity and other biological activitiesof the compounds of this invention are determined by the followingprocedures.

Membrane preparation: Human Embryonic Kidney (HEK) Cells expressing thehuman CB1 receptor under transcriptional regulation of a tetracyclineinducible promoter were grown in Dulbecco's Modified Essential Mediumwith sodium pyruvate (Invitrogen, Carlsbad, Calif.) containing 10%tetracycline free fetal bovine serum (Clonetech, Mountain View, Calif.)100 μg/ml hygromycin (Calbiochem, San Diego, Calif.), 5 μg/mlblasticidin (Invitrogen). CB1 receptor expression was induced byaddition of 1 μg/ml doxycycline (Calbiochem) and incubation for anadditional 24 hours. Cells were released from flasks using CellDissociation Buffer (Invitrogen). Cells were pelleted by centrifugationat 500×G for 5 minutes. Membranes were prepared by resuspending cells inice cold TEE Buffer (25 mM Tris pH 7.4, 5 mM EDTA, 5 mM EGTA, CompleteProtease Inhibitor (Roche, Basel, Switzerland)). Cells were lysed with12 strokes of a dounce homogenizer. Unlysed cells were pelleted bycentrifugation at 500×G for 5 minutes. Membranes were pelleted bycentrifugation at 25,000×G for 30 minutes. Membranes were resuspended inTEE, dounced 12 strokes, and pelleted a second time at 25,000×G for 30minutes. Membrane pellet was resuspended in 50 mM Tris pH 7.4, 100 mMNaCl, 3 mM MgCl₂, 0.2 mM EGTA, Complete Protease Inhibitor (Roche).Protein concentration was determined using the Micro-BCA Protein AssayKit (Pierce, Rockford, Ill.) using BSA as a standard. Membranes werequick frozen and stored at −80 degrees Celsius until use.Binding experiments: 50 μl of test compound was incubated with 50 μl, of[³H] CP-55,940 (Perkin Elmer, Boston, Mass.) (final concentration 500pM) and 150 μl of membrane homogenate (1 μg/well) in polypropylene96-well plates (Corning, Acton, Mass.). Final reaction conditions were50 mM Tris pH 7.4, 100 mM NaCl, 3 mM MgCl₂, 0.2 mM EGTA, 0.04% BSA.Nonspecific binding was determined by incubation with 50 μM WIN-55,212-2(Tocris, Ellisville, Mo.). After incubation at room temperature for 60minutes reactions were harvested by vacuum filtration through UnifilterGF/B-96 filters (Perkin Elmer) that had been presoaked in assay buffercontaining 0.5% BSA (Sigma, St. Louis, Mo.) using a FilterMate PlateHarvester (Perkin Elmer). Filters were rinsed 4 times with 50 mM Tris pH7.4, 0.025% Tween20 and dried at 50 degrees Celsius for at least 30minutes. 40 μl of Microscint-20 (Perkin Elmer) was added per well, andplates were counted using a Top-Count Microplate Scintillation Counter(Perkin Elmer). Binding data were analyzed and EC₅₀ and K_(i) valuescalculated using Graph Pad Prism 4.0 Software.

GTPγS Binding:

Membrane preparation: CHO cells expressing the human CB1 receptor weregrown to 80% confluence in Ham's F-12 Nutrient Medium (Invitrogen)containing 10% fetal bovine serum (Invitrogen), 1% pen/strep(Invitrogen), 1% Nonessential amino acids (Invitrogen) and 500 μg/mlG418 (Invitrogen). Cells were released from flasks using CellDissociation Buffer (Invitrogen). Cells were pelleted by centrifugationat 500×G for 5 minutes. Membranes were prepared by resuspending cells inice cold Assay Buffer (25 mM Tris pH 7.4, 5 mM EDTA, 5 mM EGTA, CompleteProtease Inhibitor (Roche)). Cells were lysed with 12 strokes of adounce homogenizer. Unlysed cells were pelleted by centrifugation at500×G for 5 minutes. Membranes were pelleted by centrifugation at25,000×G for 30 minutes. Membranes were resuspended in TEE, dounced 12strokes, and pelleted a second time at 25,000×G for 30 minutes. Membranepellet was resuspended in 50 mM Tris pH 7.4, 100 mM NaCl, 3 mM MgCl₂,0.2 mM EGTA, Complete Protease Inhibitor (Roche). Protein concentrationwas determined using the Micro-BCA Protein Assay Kit (Pierce) using BSAas a standard. Membranes were frozen and stored at −80 degrees Celsiusuntil use.GTPγS Binding: 40 μl of test compound was incubated with 20 μl of [³⁵S]GTPγS (Perkin Elmer) (1250 Ci/millimole) and 140 μl of membranehomogenate (5 ug/well) in polypropylene 96-well plates (Corning). Finalreaction conditions were 50 mM Tris pH 7.4, 100 mM NaCl, 3 mM MgCl₅, 0.2mM EGTA, 0.04% BSA. After incubation at 37 degrees Celsius for 45minutes reactions were harvested by vacuum filtration through UnifilterGF/B-96 filters (Perkin Elmer) using a FilterMate Plate Harvester(Perkin Elmer). Filters were rinsed 4 times with ice cold 50 mM Tris pH7.4, 3 mM MgCl₂, 0.2 mM EGTA and dried at 50 degrees Celsius for atleast 30 minutes. 40 μl of Microscint-20 (Perkin Elmer) was added perwell, and plates were counted using a Top-Count Microplate ScintillationCounter (Perkin Elmer). Binding data were analyzed and EC₅₀ values werecalculated using Graph Pad Prism 4.0 Software.

The above protocol assays were used to determine biological activity.The Ki towards human CB1 receptors for certain compounds of theinvention are measured to be 0.01-1000 nM. The EC50 towards human CB1receptors in the GTPγS assay for certain compounds of the invention aremeasured to be 0.1-5000 nM. Table 1 shows certain biological activitiesfor some of the exemplified compounds.

TABLE Example Number CB1 Ki (nM) GTPγS EC50 (nM) 132 3.4 12.7 162 0.9515.0 165 0.82 27.4 166 2.52 31.47 167 2.66 44.9 169 0.28 1.00 170 0.281.86 172 0.77 7.80 173 0.34 2.50 174 0.32 8.3 176 2.22 82.4 178 8.45 137182 17 267 188 1.9 87.7 189 88.4 1020 190 8.09 406 191 10.5 394 193 67.4622 197 0.78 13.2 198 5.79 46.5 199 0.9 40.1 200 0.52 96.9 201 4.94 45.3202 4.52 20.1 203 8.23 74.1 205 69 422 217 1.28 3.2 218 1.8 13.5 223 1021860 224 29.9 176 226 5.34 62.1 227 10.2 245 266 109 >2850 26718.4 >10000 268 130 2580 269 2.95 24 270 17.2 399 271 1.28 6.53 272 5845.4 273 57.5 244 276 0.374 5.8 280 31 136 290 19.2 25.1 292 2.09 75.1293 1.45 32.4 298 5.27 88.6 300 41 260 301 5.25 268 302 82.3 407 3035.71 36.6 304 0.15 0.87 305 0.18 1.74 306 0.31 3.45 307 1.85 49.5 3085.38 20.5 310 30.2 173 311 2.03 57 312 69.5 380 317 12 83.6 318 23.9 230319 5.17 96.3 320 4.2 98.6 327 36 >10000 328 5.94 167 329 28 606 33712.1 6490 341 24.7 355 345 52.8 1150 347 9.5 229 348 5.64 60.1 349 19.1157 350 13.4 131 355 6.72 361 356 16.6 219 357 2.4 123 359 3.06 79.2 36019.3 149 361 24.7 249 362 3.7 106 363 0.36 4.74 365 95.1 1030

EXAMPLES

The invention is illustrated in the following non-limiting examples inwhich, unless stated otherwise: all operations were carried out at roomor ambient temperature, that is, in the range of 18-25 degrees Celsius;evaporation of solvent was carried out using a rotary evaporator underreduced pressure with a bath temperature of up to 60 degrees Celsius;reactions were monitored by thin layer chromatography (TLC) and reactiontimes are given for illustration only; melting points (mp) given areuncorrected (polymorphism may result in different melting points); thestructure and purity of all isolated compounds were assured by at leastone of the following techniques: TLC (Merck silica gel 60 F₂₅₄ precoatedTLC plates or Merck NH₂ gel (an amine coated silica gel) F₂₅₄, precoatedTLC plates), mass spectrometry, nuclear magnetic resonance spectra(NMR), infrared absorption spectra (IR) or microanalysis. Yields aregiven for illustrative purposes only. Workup with a cation-exchangecolumn was carried out using SCX cartridge (Varian BondElute), which waspreconditioned with methanol. Flash column chromatography was carriedout using Merck silica gel 60 (63-200 μm), Wako silica gel 300HG (40-60μm), Fuji Silysia NH gel (an amine coated silica gel) (30-50 μm),Biotage KP-SIL (32-63 μm) or Biotage AMINOSILICA (an amine coated silicagel) (40-75 μm). Preparative TLC was carried out using Merck silica gel60 F₂₅₄ precoated TLC plates (0.5 or 1.0 mm thickness). Low-resolutionmass spectral data (EI) were obtained on an Integrity (Waters) massspectrometer. Low-resolution mass spectral data (ESI) were obtained onZMD™ or ZQ™ (Waters) and mass spectrometer. NMR data were determined at270 MHz (JEOL JNM-LA 270 spectrometer), 300 MHz (JEOL JNM-LA300spectrometer) or 600 MHz (Bruker AVANCE 600 spectrometer) usingdeuterated chloroform (99.8% D) or dimethylsulfoxide (99.9% D) assolvent unless indicated otherwise, relative to tetramethylsilane (TMS)as internal standard in parts per million (ppm); conventionalabbreviations used are: s=singlet, d=doublet, t=triplet, q=quartet,quint=quintet, m=multiplet, bs=broad singlet, etc. IR spectra weremeasured by a Fourier transform infrared spectrophotometer (ShimazuFTIR-8300). Chemical symbols have their usual meanings; bp (boilingpoint), mp (melting point), rt (room temperature), L (liter(s)), mL(milliliter(s)), g (gram(s)), mg (milligram(s)), mol (moles), mmol(millimoles), eq. (equivalent(s)), quant. (quantitative yield).Following abbreviations may be used in examples: CDI(N,N′-carbonyldiimidazole), DMF (N,N-dimethylformamide), DMSO(dimethylsulfoxide), EDAPC(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride), EtOH(ethanol), HOBt (1-Hydroxy-1H-benzotriazole), MeOH (methanol), and THF(tetrahydrofuran). Rt means retention time measured by LC/MS (Waters2790) under the following condition;

Column: Xterra, C18, 5 μm, 4.6×50 mm (40 degrees Celsius)

flow: 2.0 mL/min

Gradient: Water/MeOH/1% HCO₂H aq.=90/5/5 to 0/95/5

Total run time: 2.5 minutes.

Example 1N-[(1S,2S)-1-(Aminocarbonyl)-2-methylbutyl]-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamidehydrochloride

STEP 1. N-(2-Morpholin-4-ylethyl)-2-nitroaniline

To a mixture of 1-fluoro-2-nitrobenzene (6 g, 43.0 mmol) and potassiumcarbonate (12 g, 86 mmol) in THF (80 mL) was added4-(2-aminoethyl)morpholine (6.8 mL, 52.0 mmol) at 0 degrees Celsius. Themixture was stirred for 25 hours at room temperature. Then the mixturewas filtered through a pad of Celite and concentrated in vacuo. Theresidue was purified by column chromatography on silica get eluting withhexane/ethyl acetate (2/1) to afford 10.4 g (97%) of the title compound.

¹H-NMR (270 MHz, CDCl₃) δ 8.50 (bs, 1H), 8.18 (dd, J=8.6, 1.49 Hz, 1H),7.47-7.41 (m, 1H), 6.82 (d, J=8.6 Hz, 1H), 6.67-6.62 (m, 1H), 3.78-3.74(m, 4H), 3.40-3.34 (m, 2H), 2.73 (t, J=6.1 Hz, 2H), 2.55-2.52 (m, 4H).

MS (ESI) m/z 252 (M+H)⁺.

STEP 2. N-(2-Morpholin-4-ylethyl)benzene-1,2-dimanine

To a solution of N-(2-morpholin-4-ylethyl)-2-nitroaniline (10 g, 42mmol) in THF (100 mL) was added 10% Pd/C (1 g). The flask was evacuatedand flushed with H₂ gas and this process was repeated three times. Theflask was filled with H₂ gas (4 atm) and stirred for 4 hours at roomtemperature. Then the reaction mixture was filtered through a pad ofCelite and concentrated in vacuo to give the title compound (crude; 9.0g)

¹H-NMR (300 MHz, CDCl₃) δ 6.82-6.64 (m, 4H), 3.71 (t, J=4.6 Hz, 4H),3.40 (bs, 2H), 3.19-3.15 (m, 2H), 2.69-2.65 (m, 2H), 2.48 (t, J=4.6 Hz,4H).

MS (ESI) m/z 222 (M+H)⁺.

STEP 3, 1-(2-Morpholin-4-ylethyl)-1,3-dihydro-2H-benzimidazol-2-one

To a solution of N-(2-morpholin-4-ylethyl)benzene-1,2-dimanine in THF(100 mL) was added CDI (10 g, 62 mmol) and the mixture was stirred atroom temperature. After 23 hours, the mixture was evaporated in vacuoand to the residue was added water (100 mL) at 0 degrees Celsius. Themixture was extracted with ethyl acetate (100 mL×2) and the combinedorganic layers were washed with water (50 mL), brine (50 mL), dried oversodium sulfate, filtered and concentrated in vacuo. The residue waspurified by column chromatography on silica gel eluting withdichloromethane/methanol (30/1) to afford 8.5 g (83%) of the titlecompound.

¹H-NMR (300 MHz, CDCl₃) δ 10.4 (s, 1H), 7.13-7.01 (m, 4H), 4.03 (t,J=6.8 Hz, 2H), 3.70 (t, J=4.6 Hz, 4H), 2.72 (t, J=6.8 Hz, 2H), 2.57 (t,J=4.6 Hz, 4H).

MS (ESI) m/z 248 (M+H)⁺, 246 (M−H)⁻.

IR (KBr)ν_(max) 2851, 1697, 1491, 1402, 1117 cm⁻¹.

mp 131.0 degrees Celsius.

STEP 4.N-[(1S,2S)-1-(Aminocarbonyl)-2-methylbutyl]-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamidehydrochloride

To a solution of1-(2-morpholin-4-ylethyl)-1,3-dihydro-2H-benzimidazol-2-one (530 mg, 2.1mmol) in dichloromethane (8 mL) were added triethylamine (1.0 mL, 7.0mmol) and 4-nitrophenyl chloroformate (470 mg, 2.3 mmol) at 0 degreesCelsius and the mixture was stirred for 3 hours at room temperature Thento this mixture was added a mixture of L-isoleucinamide hydrochloride(430 mg, 2.6 mmol) and triethylamine (0.6 mL, 4.3 mmol) indichloromethane (4 mL) at 0 degrees Celsius and stirred roomtemperature. After 22 hours, the reaction was quenched by addition ofwater (50 mL) and extracted with dichloromethane (50 mL×2). The combinedorganic layers were washed with water (20 mL×3), brine (20 mL) and driedover sodium sulfate, filtered and concentrated. The residue was purifiedby column chromatography on silica gel eluting with hexane/ethyl acetate(1/4) to afford 600 mg (70%) of free form of the title compound. Theobtained compound was dissolved in ethyl acetate (1 mL) and to thissolution was added 4N HCl in ethyl acetate (0.4 mL) to form white solidwhich was filtered and dried in vacuo to give the title compound (600mg).

¹H-NMR (300 MHz, CDCl₃) δ 10.91 (bs, 1H), 9.00 (d, J=8.1 Hz, 1H), 8.06(d, J=7.8 Hz, 1H), 7.68 (s, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.31-7.18 (m,3H), 4.38-4.30 (m, −3H), 4.04-3.99 (m, 2H), 3.78-3.70 (m, 2H), 3.65-3.57(m, 2H), 3.53-3.45 (m, 2H), 3.21-3.17 (m, 2H), 1.89-1.83 (m, 1H),1.56-1.45 (m, 1H), 1.17-1.03 (m, 1H), 0.94 (d, J=6.9 Hz, 3H), 0.89 (t,J=7.2 Hz, 3H).

MS (ESI) m/z 404 (M+H)⁺.

Anal. calcd. for C₂₀H₂₉N₅O₄ (+0.8H₂O, 1.0 HCl): C, 52.87; H, 7.01; N,15.41; O, 16.90; Cl, 7.80.

Found: C, 53.00; H, 7.23; N, 15.01.

Example 2 MethylN-{[3-(2-Morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-yl]carbonyl}-L-isoleucinate

The titled compound was prepared according to the procedure described inStep 4 of example 1 from methyl L-isoleucinate hydrochloride.

¹H-NMR (300 MHz, CDCl₃) δ 9.29 (d, J=8.1 Hz, 1H), 8.20-8.17 (m, 1H),7.24-7.13 (m, 2H), 7.05-7.02 (m, 1H), 4.62 (dd, J=8.1, 4.8 Hz, 1H), 4.02(t, J=6.9 Hz, 2H), 3.78 (s, 3H), 3.69-3.66 (m, 4H), 2.70 (t, J=6.6 Hz,2H), 2.54 (bs, 4H), 2.12-2.05 (m, 1H), 1.61-1.48 (m, 1H), 1.35-1.24 (m,1H), 1.03 (d, J=6.9 Hz, 3H), 0.97 (t, J=7.2 Hz, 3H).

MS (ESI) m/z 419 (M+H)⁺.

Example 3N-{(1S,2S)-1-[(Dimethylamino)carbonyl]-2-methylbutyl}-3-(2-morpholin-4-ylethyl)-oxo-2,3-dihydro-1H-benzimidazol-1-carboxamide

STEP 1.N-{[3-(2-Morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}-L-isoleucinehydrochloride

A suspension of methylN-{[3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}-L-isoleucinate(Example 2) in 4N HCl (4 mL) and acetic acid (4 mL) was refluxed for 24hours. Then it was cooled to room temperature and evaporated to dryness.Recrystallization from ethyl acetate and hexane followed by filtrationgave 510 mg (81%) of the title compound as white solid.

¹H-NMR (300 MHz, DMSO-d₆) δ 9.08 (d, J=8.1 Hz, 1H), 8.35 (bs, 1H), 8.05(d, J=7.2 Hz, 1H), 7.53 (d, J=7.5 Hz, 1H), 7.29 (t, J=7.5 Hz, 1H), 7.21(t, J=7.2 Hz, 1H), 4.43-4.39 (m, 3H), 4.07-3.95 (m, 2H), 3.30-3.05 (m,10H), 2.00-1.95 (m, 1H), 1.53-1.44 (m, 1H), 1.28-1.15 (m, 1H), 0.95 (s,3H), 0.93 (s, 3H).

MS (ESI) m/z 405 (M+H)⁺.

IR (KBr)ν_(max) 1732, 1639, 1387, 1184 cm⁻¹

[α]_(D) ²⁷+24.0° (c 0.275, methanol).

STEP 2.N-{(1S,2S)-1-[(Dimethylamino)carbonyl]-2-methylbutyl}-3(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

To a solution of N-{[3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1benzimidazol-1-yl]carbonyl}-L-isoleucine hydrochloride (Step 1, 62 mg,0.14 mmol) in DMF (1 mL) was added CDI (27 mg, 0.17 mol) at roomtemperature. After 2 hours, to the mixture was added aq. dimethylamine(40%, 20 μL) and stirred for further 14 hours. Then to the mixture wasadded water (10 mL). The mixture was extracted with ethyl acetate (20mL×2) and the combined organic layers were washed with brine (10 mL),dried over sodium sulfate, filtered and concentrated. The residue waspurified by preparative TLC eluting with dichloromethane/methanol (10/1)to afford 33 mg (54%) of the title compound.

¹H-NMR (300 MHz, DMSO-d₆) δ 9.14 (d, J=8.4 Hz, 1H), 8.02 (d, J=7.5 Hz,1H), 7.35 (d, J=7.8 Hz, 1H), 7.24 (t, J=7.2 Hz, 1H), 7.15 (t, J=7.8 Hz,1H), 4.83 (dd, J=8.4, 6.3 Hz, 1H), 4.02 (t, J=6.0 Hz, 2H), 3.49 (t,J=4.8 Hz, 4H), 3.12 (s, 3H), 2.87 (s, 3H), 2.63-2.58 (m, 2H), 2.46-2.43(m, 4H), 1.85-1.75 (m, 1H), 1.57-1.48 (m, 1H), 1.17-1.07 (m, 1H), 0.93(d, J=6.6 Hz, 3H), 0.87 (t, J=7.5 Hz, 3H).

MS (ESI) m/z 432 (M+H)⁺.

Example 4N-[(1S)-1-Aminocarbonyl)-2,2-dimethylpropyl]-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

STEP 1, Benzyl [(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]carbamate

To a solution of N-[(benzyloxy)carbonyl]-tert-leucine (preparedaccording to the procedure in the literature; Emily, M. S. et al.Tetrahedron 2001, 57, 5303-5320.; 3.7 g, 14 mmol) in DMF (80 mL) wereadded ammonium chloride (900 mg, 17 mmol), triethylamine (5.9 mL, 42mmol), HOBt (2.8 g, 18 mmol) and EDAPC (3.1 g, 18 mmol) and stirred atroom temperature. After 17 hours, the reaction mixture was quenched byaddition of saturated aqueous sodium bicarbonate (100 mL) and extractedwith ethyl acetate (100 mL×3). The combined organic layers were washedwith water (100 mL×3), brine (50 mL), dried over sodium sulfate,filtered and concentrated in vacuo. The residue was purified by columnchromatography on silica gel eluting with hexane/ethyl acetate (211-1/1)to afford 3.0 g (82%) of the title compound.

MS (ESI) m/z 265 (M+H)⁺.

STEP 2, tert-Leucinamide

To a solution of benzyl[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]carbamate (Step 1, 3.7 g, 14mmol) in THF (40 mL) was added 10% Pd/C (710 mg). The flask wasevacuated and flushed with H₂ gas and this process was repeated threetimes. The flask was filled with H₂ gas (4 atm) and stirred for 3 hoursat room temperature. Then the reaction mixture was filtered through apad of Celite and concentrated in vacuo to give the title compound aswhite solid (crude; 1.8 g)

¹H-NMR (300 MHz, DMSO-d₆) δ 6.59 (bs, 1H), 5.92 (bs, 1H), 3.12 (s, 1H),1.02 (s, 1H).

MS (ESI) m/z 131 (M+H).

STEP 3.N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamidehydrochloride

The title compound was prepared according to the procedure described inStep 4 of Example 1 from L-tert-leucinamide.

¹H-NMR (270 MHz, CDCl₃, the value of free form of the title compound) δ9.45 (d, J=7.8 Hz, 1H), 8.19-8.16 (m, 1H), 7.25-7.14 (m, 2H), 7.05 (d,J=7.6 Hz, 1H), 5.83 (bs, 1H), 5.53 (bs, 1H), 4.22 (d, J=8.1 Hz, 1H),4.02 (t, J=6.8 Hz, 2H), 3.68 (t, J=4.6 Hz, 4H), 2.73-2.68 (m, 2H),2.60-2.49 (m, 4H), 1.15 (s, 9H).

MS (ESI) m/z 404 (M+H)⁺.

Anal. calcd. for C₂₀H₂₉N₅O₄ (+1.0H₂O, 1.0 HCl): C, 52.45; H, 7.043; N,15.29; O, 17.47; Cl, 7.74.

Found: C, 52.41; H, 7.21; N, 14.98.

[α]_(D) ²⁵+29.5° (c 0.325, methanol).

Example 5 Methyl3-methyl-N-{[3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}-L-valinate

The title compound was prepared according to the procedure described inStep 4 of Example 1 from methyl L-tert-leucinate. The obtained compoundwas further purified by recrystallization from hexane/ethyl acetate.

¹H-NMR (300 MHz, CDCl₃) δ 9.40 (d, J=8.4 Hz, 1H), 8.20-8.17 (m, 1H),7.25-7.08 (m, 3H), 4.44 (d, J=8.4 Hz, 1H), 4.10-3.99 (m, 2H), 3.77 (s,3H), 3.73-3.65 (m, 4H), 2.77-2.66 (m, 2H), 2.62-2.52 (m, 4H), 1.09 (s,9H).

MS (ESI) m/z 419 (M+H)⁺.

Anal. calcd. for C₂₁H₃₀N₄O₅ (+0.5H₂O): C, 59.00; H, 7.31; N, 13.11; O,20.58. Found: C, 59.24; H, 7.23; N, 13.15.

IR (KBr)ν_(max) 1728, 1553, 1398, 1159 cm⁻¹.

Example 6N-{(1S)-2,2-Dimethyl-1-[(methylamino)carbonyl]propyl-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described inExample 3 from Methyl3-methyl-N-{[3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}-L-valinate(Example 5) and aqueous methylamine (40%).

¹H-NMR (270 MHz, CDCl₃) δ 9.43 (d, J=8.4 Hz, 1H), 8.18-8.15 (m, 1H),7.25-7.07 (m, 3H), 5.85-5.75 (bs, 1H), 4.15 (d, J=8.4 Hz, 1H), 4.10-3.95(m, 2H), 3.75-3.62 (m, 4H), 2.84 (d, J=4.59 Hz, 3H), 2.78-2.45 (m, 6H),1.12 (s, 9H).

MS (ESI) m/z 418 (M+H)⁺.

Example 7N-{(1S)-1-[(Dimethylamino)carbonyl]-2,2-dimethylpropyl}-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described inExample 3 fromMethyl-3-methyl-N-{[3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}-L-valinate(Example 5).

¹H-NMR (270 MHz, CDCl₃) δ 9.48 (d, J=9.2 Hz, 1H), 8.18-8.15 (m, 1H),7.23-7.12 (m, 2H), 7.03 (d, J=7.6 Hz, 1H), 4.93 (d, J=9.2 Hz, 1H),4.05-3.99 (m, 2H), 3.69-3.66 (m, 4H), 3.23 (s, 3H), 3.00 (s, 3H),2.74-2.66 (m, 2H), 2.58-2.48 (m, 4H), 1.11 (s, 9H)

MS (ESI) m/z 432 (M+H)⁺.

Example 8N-[(1S,2S)-1-(Aminocarbonyl)-2-methylbutyl]-2-oxo-3-(2-piperidin-1-ylethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamidehydrochloride

STEP 1. 1-(2-Piperidin-1-ylethyl)-1,3-dihydro-2H-benzimidazol-2-one

The title compound was prepared according to the procedure described inSteps 1 to 3 of Example 1 from 1-(2-aminoethyl)piperidine.

¹H-NMR (300 MHz, CDCl₃) δ 10.82-10.72 (m, 1H), 7.07-7.04 (m, 4H),4.06-4.01 (m, 2H), 2.71-2.65 (m, 2H), 2.55-2.50 (m, 4H), 1.62-1.58 (m,4H), 1.45-1.43 (m, 2H).

MS (ESI) m/z 246 (M+H)⁺.

STEP 2.N-[(1S,2S)-1-(Aminocarbonyl)-2-methylbutyl]-2-oxo-3-(2-piperidin-1-ylethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamidehydrochloride

The title compound was prepared according to the procedure described inSteps 4 of Example 1 from1-(2-Piperidin-1-ylethyl)-1,3-dihydro-2H-benzimidazol-2-one (Step1).

¹H-NMR (270 MHz, CDCl₃) δ 12.47 (bs, 1H), 9.06 (d, J=8.1 Hz, 1H), 8.10(d, J=7.6 Hz, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.24-7.11 (m, 2H), 6.48 (bs,1H), 5.69 (bs, 1H), 4.55-4.53 (m, 2H), 4.42 (dd; J=8.1, 5.4 Hz, 1H),3.80-3.50 (m, 2H), 3.40-3.10 (m, 2H), 2.86-2.65 (m, 2H), 2.26-1.48 (m,7H), 1.34-1.17 (m, 2H), 1.05 (d, J=7.0 Hz, 3H), 0.97 (t, J=7.3 Hz, 3H).

MS (ESI) m/z 402.4 (M+H)⁺.

Anal. calcd. for C₂₁H₃₁N₅O₃ (+0.5H₂O, 1 HCl, 0.2 C₄H₈O₂): C, 56.36; H,7.51; N, 15.07; O, 13.43; Cl, 7.63. Found: C, 56.28; H, 7.72; N, 14.96.

mp 217.1 degrees Celsius

Example 9N-[(1S,2S)-1-(Aminocarbonyl)-2-methylbutyl]-4-methoxy-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamidehydrochloride

STEP 1. 2-Bromo-N-(2-methoxy-6-nitrophenyl)acetamide

To a flask was added sodium hydride (60% dispersion in mineral oil, 610mg, 15 mmol) and hexane (2 mL) at 0 degrees Celsius. The supernatantliquid was decanted and the residue was dried under reduced pressure. Tothis was added THF (20 mL) and a solution of 2-methoxy-6-nitroaniline (2g, 12 mmol, Kubo, K. et al. J. Med. Chem. 1993, 36, 1772-1784) in THF(20 mL) at 0 degrees Celsius and stirred at room temperature for 2hours. To this mixture was added bromoacetyl bromide (1.2 mL, 14 mmol)at 0 degrees Celsius and stirred at room temperature for 3 hours. Thenthe reaction mixture was quenched by addition of water (100 mL) andextracted with ethyl acetate (100 mL×2). The combined organic layerswere washed with brine (100 mL), dried over sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel eluting with hexane/ethyl acetate (2/1-1/1) to afford 2.9g (85%) of the title compound.

¹H-NMR (300 MHz, CDCl₃) δ 8.62 (bs, 1H), 7.56 (dd, J=8.2, 1.1 Hz, 1H),7.34 (dd, J=8.4, 8.2 Hz, 1H), 7.19 (dd, J=8.4, 1.1 Hz, 1H), 4.04 (s,2H), 3.96 (s, 3H).

STEP 2. N-(2-Methoxy-6-nitrophenyl)-2-morpholin-4-ylacetamide

To a solution of 2-bromo-N-(2-methoxy-6-nitrophenyl)acetamide (Step1,8.8 g, 30 mmol) in THF (240 mL) was added morpholin (11 mL, 122 mmol) at0 degrees Celsius and warmed to room temperature. After 2.5 hours, thereaction mixture was quenched by addition of water (200 mL) andextracted with ethyl acetate (200 mL×2). The combined organic layerswere washed with water (200 mL), brine (100 mL) dried over sodiumsulfate, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel eluting with hexane/ethyl acetate(2/1) to afford 6.7 g (75%) of the title compound.

¹H-NMR (270 MHz, CDCl₃) δ 9.51 (bs, 1H), 7.53 (dd, J=8.4, 8.1 Hz, 1H),7.29 (dd, J=8.4, 8.1 Hz, 1H), 7.17 (dd, J=8.4, 1.1 Hz, 1H), 3.94 (s,3H), 3.84-3.81 (m, 4H), 3.18 (s, 2H), 2.68-2.65 (m, 4H).

MS (ESI) m/z 296 (M+H)⁺, 294 (M−H)⁻.

STEP 3. 3-Methoxy-N²-(2-morpholin-4-ylethyl)benzene-1,2-diamine

To a suspension of lithium aluminum hydride (5.2 g, 136 mmol) in THF (35mL) was added a solution ofN-(2-methoxy-6-nitrophenyl)-2-morpholin-4-ylacetamide (Step 2, 6.7 g, 23mmol) in THF (40 mL) at 0 degrees Celsius and stirred at reflux for 2hours. Then to this mixture was added water (5.2 mL) followed byaddition of 15% sodium hydroxide (5.2 mL), water (15.6 mL) at 0 degreesCelsius. The mixture was diluted with ethyl acetate (100 mL) and stirredfor 3 hours at room temperature. The resultant mixture was filtered andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel eluting with dichloromethane/methanol (30/1) to afford 2.5g (44%) of the title compound.

¹H-NMR (300 MHz, CDCl₃) δ 6.82 (t, J=8.1 Hz, 1H), 6.39-6.31 (m, 2H),3.79 (s, 3H), 3.77-3.69 (m, 4H), 3.02-2.98 (m, 2H), 2.53-2.50 (m, 6H).

MS (ESI) m/z 252 (M+H)⁺.

STEP 4.7-Methoxy-1-(2-morpholin-4-ylethyl)-1,3-dihydro-2-H-benzimidazol-2-one

The title compound was prepared according to the procedure described inStep 3 of Example 1 from3-Methoxy-N²-(2-morpholin-4-ylethyl)benzene-1,2-diamine (Step 3).

¹H-NMR (300 MHz, CDCl₃) δ 8.98 (bs, 1H), 6.98 (dd, J=8.3, 7.9 Hz, 1H),6.72 (dd, J=7.9, 0.7 Hz, 1H), 6.63 (d, J=8.2 Hz, 1H), 4.21 (t, J=7.1 Hz,2H), 3.90 (s, 3H), 3.71-3.68 (m, 4H), 2.71 (t, J=7.1 Hz, 2H), 2.58-2.55(m, 4H).

MS (ESI) m/z 278 (M+H)⁺.

STEP 5.N-[(1S,2S)-1-(Aminocarbonyl)-2-methylbutyl]-4-methoxy-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamidehydrochloride

The title compound was prepared according to the procedure described inSep 4 of Example 1 from7-Methoxy-1-(2-morpholin-4-ylethyl)-1,3-dihydro-2-H-benzimidazol-2-one(Step 4) and L-isoleucinamide.

¹H-NMR (300 MHz, CDCl₃) δ 12.70 (bs, 1H), 9.12 (d, J=8.1 Hz, 1H), 7.84(d, J=8.4 Hz, 1H), 7.19 (bs, 1H), 7.09 (t, J=8.4 Hz, 1H), 6.74 (d, J=8.4Hz, 1H), 5.69 (bs, 1H), 4.69-4.55 (m, 2H), 4.44 (dd, J=8.4, 4.5 Hz, 4H),4.37-4.03 (m, 5H), 3.94 (s, 3H), 3.60-3.40 (m, 2H), 3.30-3.15 (m, 1H),3.10-2.40 (m, 2H), 2.27-2.16 (m, 1H), 1.67-1.54 (m, 1H), 1.36-1.16 (m,1H), 1.06 (d, J=6.9 Hz, 3H), 0.97 (t, J=7.5 Hz, 3H).

MS (ESI) m/z 434 (M+H)⁺.

Anal. calcd. for C₂₁H₃₁N₅O₅ (+0.5H₂O, 1 HCl, 0.1 C₄H₈O₂): C, 52.69; H,6.98; N, 14.36; O, 18.70; Cl, 7.27. Found: C, 52.33; H, 7.20; N, 14.01.

Example 10N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-[2-tetrahydro-2H-pyran-4-yl)ethyl]-2,3-dihydro-1H-benzimidazole-1-carboxamide

STEP 1.1-[2-(Tetrahydro-2H-pyran)-4-ylethyl]-1,3-dihydro-2H-benzimidazol-2-one

The title compound was prepared according to the procedure described inSteps 1 to 3 of Example 1 from 2-(tetrahydro-2H-pyran-4-yl)ethanamine.

MS (ESI) m/z 247 (M+H)⁺, 245 (M−H)⁻.

STEP 2.N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-[2-(tetrahydro-2-pyran-4-yl)ethyl]-2,3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described inStep 4 of Example 1 from1-(2-(Tetrahydro-2H-pyran-4-ylethyl)-1,3-dihydro-2H-benzimidazol-2-one(Step 1).

¹H-NMR (270 MHz, CDCl₃) δ 9.45 (d, J=8.1 Hz, 1H), 8.17 (d, J=7.56 Hz,1H), 7.26-7.14 (m, 2H), 7.00 (dd, J=8.1, 1.6 Hz, 1H), 5.99 (bs, 1H),5.23 (bs, 1H), 4.24 (d, J=8.1 Hz, 1H), 4.00-3.88 (m, 4H), 3.38 (t,J=11.6 Hz, 2H), 1.77-1.69 (m, 4H), 1.64-1.53 (m, 1H), 1.45-1.30 (m, 2H),1.15 (s, 9H).

MS (ESI) m/z 403 (M+H)⁺.

Anal. calcd. for C₂₁H₃₀N₄O₄ (+0.1H₂O): C, 62.39; H, 7.53; N, 13.86; O,16.23. Found: C, 62.21; H, 7.59; N, 13.70.

Example 11N-[(1S)-(Aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclopropylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

STEP 1. 1-(cyclopropylmethyl)-1,3-dihydro-2H-benzimidazol-2-one

The title compound was prepared according to the procedure described inSteps 1 to 3 of Example 1 from 1-cyclopropylmethanamine.

¹H-NMR (300 MHz, CDCl₃) δ 7.15-7.03 (m, 4H), 3.79 (d, J=7.0 Hz, 2H),1.30-1.21 (m, 1H), 0.59-0.50 (m, 2H), 0.48-0.39 (m, 2H).

MS (ESI) m/z 189 (M+H)⁺.

STEP 2.N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclopropylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described instep 4 of Example 1 from1-(cyclopropylmethyl)-1,3-dihydro-2H-benzimidazol-2-one (Step 1).

¹H-NMR (270 MHz, CDCl₃) δ 9.48 (d, J=7.8 Hz, 1H), 8.17 (d, J=7.83 Hz,1H), 7.25-7.13 (m, 2H), 7.10-7.06 (m, 1H), 5.96 (bs, 1H), 5.65 (bs, 1H),4.23 (d, J=7.8 Hz, 1H), 3.79 (d, J=7.02 Hz, 2H), 1.33-1.21 (m, 1H), 1.15(s, 9H), 0.62-0.55 (m, 2H), 0.50-0.42 (m, 2H).

MS (ESI) m/z 345 (M+H)⁺.

Anal. calcd. for C₁₈H₂₄N₃O₃ (+0.1H₂O): C, 62.45; H, 7.05; N, 16.18; O,14.33. Found: C, 62.26; H, 7.06; N, 16.08.

Example 12N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-3-(3-methylbutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

STEP 1. 1-(3-methylbutyl)-1,3-dihydro-2H-benzimidazol-2-one

The title compound was prepared according to the procedure described inthe literature (Meth-Cohn, O.; Smith, D. I. J.C.S. Perkin Trans. 1,1982, 261-270; Vernin G. et al. J. Heterocyclic Chem. 1981, 18, 85-89.)from 1-bromo-3-methylbutane.

¹H-NMR (300 MHz, CDCl₃)

9.86 (br, 1H), 7.14-6.98 (m, 4H), 3.94-3.88 (m, 2H), 1.72-1.62 (m, 3H),1.00 (d, J=6.1 Hz, 6H).

STEP 2N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-3-(3-methylbutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

To a solution of 1-(3-methylbutyl)1,2-dihydro-2H-benzimidazol-2-one(Step 1, 140 mg, 0.69 mmol) in dichloromethane (2.5 mL) were addedtriethylamine (0.32 mL, 2.3 mmol) and 4-nitrophenyl chloroformate (150mg, 0.76 mmol) at 0 degrees Celsius and the mixture was stirred for 4hours at room temperature. Then to this mixture was added a solution ofL-tert-leucinamide (steps 1 and 2 in example 4, 99 mg, 0.76 mmol) indichloromethane, (2 mL) at 0 degrees Celsius and stirred rt. After 22 h,the reaction was quenched by addition of water (20 mL) and extractedwith ethyl acetate (30 mL×2). The combined organic layers were washedwith water (20 mL×3), brine (20 mL) and dried over sodium sulfate,filtered and concentrated. The residue was purified by columnchromatography on silica gel eluting with hexane/ethyl acetate (3/1-1/1)to afford 240 mg (96%) of the titled compound. The obtained product wasfurther purified by recrystallization from hexane/ethyl acetate to give220 mg of the title compound.

¹H-NMR (270 MHz, CDCl₃) δ 9.48 (d, J=7.8 Hz, 1H), 8.16 (d, J=7.56 Hz,1H), 7.25-7.12 (m, 2H), 7.03-7.00 (m, 1H), 6.01 (bs, 1H), 5.72 (bs, 1H),4.24 (d, J=7.8 Hz, 1H), 3.99-3.81 (m, 2H), 1.71-1.61 (m, 3H), 1.15 (s,9H), 1.00 (d, J=6.2 Hz, 6H).

MS (ESI) m/z 361 (M+H)⁺.

Anal. calcd. for C₁₉H₂₈N₄O₃: C, 63.31; H, 7.83; N, 15.54; O, 13.32.Found: C, 62.94; H, 7.86; N, 15.62.

Example 13N-[(1S)-(Aminocarbonyl)-2,2-dimethylpropyl]-3-(3,3-dimethylbutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

STEP 1. 1(3,3-dimethylbutyl)-1,2-dihydro-2H-benzimidazol-2-one

The title compound was prepared according to the procedure described inthe literature (Meth-Cohn, O.; Smith, D. I. J.C.S. Perkin Trans. 1,1982, 261-270; Vernin G. et al. J. Heterocyclic Chem. 1981, 18, 85-89.)from 1-bromo-3,3-dimethylbutane.

¹H-NMR (300 MHz, CDCl₃) δ 9.7-9.5 (br, 1H), 7.14-6.96 (m, 4H), 3.94-3.88(m, 2H), 1.71-1.63 (m, 2H), 1.04 (s, 9H).

STEP 2.N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-3-(3,3-dimethylbutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described inStep 2 of Example 12 from1-(3-methylbutyl)1,2-dihydro-2H-benzimidazol-2-one (Step 1).

¹H-NMR (270 MHz, CDCl₃) δ 9.47 (d, J=8.1 Hz, 1H), 8.16 (dd, J=7.8, 1.4Hz, 1H), 7.27-7.12 (m, 2H), 6.99 (dd, J=7.3, 1.6 Hz, 1H), 6.01 (bs, 1H),5.74 (bs, 1H), 4.25 (d, J=8.1 Hz, 1H), 3.99-3.81 (m, 2H), 1.70-1.62 (m,2H), 1.15 (s, 9H), 1.04 (s, 9H).

MS (ESI) m/z 375 (M+H)⁺.

Anal. calcd. for C₂₀H₃₀N₄O₃ (+0.1H₂O): C, 63.84; H, 8.09; N, 14.89; O,13.18. Found: C, 63.47; H, 8.10; N, 14.89.

Example 14N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-3-[(1-methylpiperidin-2-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamidehydrochloride

STEP 1.1-[(1-methylpiperidin-2-yl)methyl]-1,3-dihydro-2H-benzimidazol-2-one

The title compound was prepared according to the procedure described inSteps 1 to 3 of Example 1 from 1-(1-methylpiperidin-2-yl)methanamine.

MS (ESI) m/z 246 (M+H)⁺.

STEP 2.N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-3-[(1-methylpiperidin-2-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamidehydrochloride

The title compound was prepared according to the procedure described inStep 4 of Example 1 from1-[(1-methylpiperidin-2-yl)methyl]-1,3-dihydro-2H-benzimidazol-2-one.

¹H-NMR (300 MHz, CDCl₃) δ 9.26-9.21 (m, 2H), 8.11 (d, J=8.4 Hz, 2H),7.41-7.14 (m, 6H), 6.13-5.95 (m, 2H), 5.61-5.56 (m, 2H), 4.71-4.52 (m,4H), 4.26 (d, J=8.4 Hz, 2H), 3.30-3.28 (m, 4H), 2.96 (s, 3H), 2.91 (s,3H), 2.18-1.80 (m, 14H), 1.14 (s, 18H).

MS (ESI) m/z 402 (M+H)⁺.

Anal. calcd. for C₂₁H₃₁N₅O₃(+0.8H₂O, 1.5 HCl): C, 53.60; H, 7.30; N,14.88; O, 12.92; Cl, 11.30.

Found: C, 53.99; H, 7.61; N, 14.86.

Example 15N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-methyl-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

STEP 1. 2-Methyl-N-(2-morpholin-4-ylethyl)-6-nitroaniline

A solution of 2-chloro-3-nitrotoluene (180 mg, 1.0 mmol),4-(2-aminoethyl)morpholine (0.54 mL, 4.1 mmol) and triethylamine (0.43mL, 3.1 mmol) was heated to 180 degrees Celsius by microwave for 20minutes. The resultant mixture was purified by column chromatography onsilica gel eluting with hexane/ethyl acetate (8/1-3/1) to afford 160 mg(59%) of the title compound.

MS (ESI) m/z 266 (M+H)⁺.

STEP 2.7-Methyl-1-(2-morpholin-4-ylethyl)-1,3-dihydro-2H-benzimidazol-2-one

The title compound was prepared according to the procedure described inSteps 2 to 3 of Example 1 from2-Methyl-N-(2-morpholin-4-ylethyl)-6-nitroaniline (Step 1).

¹H-NMR (300 MHz, CDCl₃) δ 9.10 (bs, 1H), 6.98-6.91 (m, 2H), 6.85-6.82(m, 1H), 4.24-4.19 (m, 2H), 3.72-3.69 (m, 4H), 2.70-2.65 (m, 2H), 2.60(s, 3H), 2.58-2.55 (m, 4H).

MS (ESI) m/z 262 (M+H)⁺.

STEP 3.N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-4-methyl-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described inStep 4 of example 1 from7-methyl-1-(2-morpholin-4-ylethyl)-1,3-dihydro-2H-benzimidazol-2-one(Step 2).

¹H-NMR (300 MHz, CDCl₃) δ 9.58 (d, J=7.8 Hz, 1H), 8.10 (d, J=7.8 Hz,1H), 7.05 (t, J=7.8 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 5.91 (bs, 1H), 5.60(bs, 1H), 4.29-4.18 (m, 3H), 3.73-3.65 (m, 4H), 2.75-2.64 (m, 2H), 2.60(s, 3H), 2.63-2.45 (m, 4H), 1.15 (s, 9H).

MS (ESI) m/z 418 (M+H)⁺.

Anal. calcd. for C₂₁H₃₁N₅O₄ (+0.5H₂O, 0.1 C₄H₈O₂): C, 59.04; H, 7.59; N,16.09; O, 17.27.

Found: C, 58.99; H, 7.35; N, 15.88.

Example 16N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-6-methyl-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamidehydrochloride

STEP 1.6-methyl-1-(2-morpholia-4-ylethyl)-1,3-dihydro-2H-benzimidazol-2-one

The title compound was prepared according to the procedure described inSteps 1 to 3 of Example 1 from 3-fluoro-4-nitrotluene.

MS (ESI) m/z 262 (M+H)⁺, 260 (M−H)⁻.

STEP 2.N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-5-methyl-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamidehydrochloride

The title compound was prepared according to the procedure described inStep 4 of Example 1 from6-methyl-1-(2-morpholin-4-ylethyl)-1,3-dihydro-2H-benzimidazol-2-one(Step 1).

¹H-NMR (300 MHz, DMSO-d₆) δ 11.47 (bs, 1H), 9.09 (d, J=9.0 Hz, 1H), 7.90(d, J=7.5 Hz, 1H), 7.70 (s, 1H), 7.37 (s, 1H), 7.22 (s, 1H), 7.00 (d,J=7.5 Hz, 1H), 4.43-4.32 (m, 2H), 4.25 (d, J=9.0 Hz, 1H), 4.07-3.95 (m,2H), 3.88-3.72 (m, 2H), 3.68-3.52 (m, 2H), 3.51-3.42 (m, 2H), 3.27-3.10(m, 2H), 2.38 (s, 3H), 1.00 (s, 9H).

MS (ESI) m/z 418 (M+H)⁺.

Anal. calcd. for C₂₁H₃₁N₅O₄ (+1.0H₂O, 1.0 HCl): C, 53.44; H, 7.26; N,14.84; O, 16.95; Cl, 7.51.

Found: C, 53.77; H, 7.32; N, 14.64.

Example 17N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-3-(3-methylbutyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-1-carboxamide

STEP 1. 3-(3-methylbutyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one

The title compound was prepared according to the procedure described inthe literature (Meth-Cohn, O.; Smith, D. I. J.C.S. Perkin Trans. 1,1982, 261-270; Vernin G. et al. J. Heterocyclic Chem. 1981, 18, 85-89.)from 1-bromo-3-methylbutane and1-isopropenyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (Israel, M.;Jones, L. C. J. Heterocyclic Chem. 1971, 8, 797.

¹H-NMR (300 MHz, CDCl₃)

10.15 (br, 1H), 8.33 (d, J=5.3 Hz, 1H), 8.33 (s, 1H), 7.09 (d, J=5.3 Hz,1H), 3.95 (t, J=7.3 Hz, 2H), 1.76-1.63 (m, 3H), 1.02 (d, J=7.0 Hz, 6H).

STEP 2.N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-3-(3-methylbutyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-1-carboxamide

The title compound was prepared according to the procedure described inStep 4 of Example 1 from3-(3-methylbutyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one.

¹H-NMR (300 MHz, CDCl₃) δ 9.34 (d, J=8.1 Hz, 1H), 8.43 (d, J=5.1 Hz,1H), 8.38 (s, 1H), 8.04 (d, J=5.1 Hz, 1H), 5.80 (bs, 1H), 5.59 (bs, 1H),4.20 (d, J=8.1. Hz, 1H), 4.00-3.90 (m, 2H), 1.76-1.65 (m, 3H), 1.15 (s,9H), 1.02 (d, J=5.7 Hz, 6H).

MS (ESI) m/z 362 (M+H)+

Anal. calcd. for C₁₈H₂₇N₆O₃ (+0.5H₂O): C, 58.36; H, 7.62; N, 18.91; O,15.12. Found: C, 58.60; H, 7.45; N, 18.94.

Example 18N-[(1S)-(Aminocarbonyl)-2,2-dimethylpropyl]-3-[2-(dimethylamino)ethyl]-4-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

STEP 1.1-[2-(dimethylamino)ethyl]-7-methyl-1,3-dihydro-2H-benzimidazol-2-one

The title compound was prepared according to the procedure described inSteps 1 to 3 of Example 1 from N,N-dimethylethylenediamine and2-chloro-3-nitrotoluene.

MS (ESI) m/z 220 (M+H)⁺.

STEP 2.N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-3-[2-(dimethylamino)ethyl]-4-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described inStep 4 of Example 1 from7-methyl-1-[2-dimethylamino)ethyl-1,3-dihydro-2H-benzimidazol-2-one(Step 1) and L-tert-leucinamide.

¹H-NMR (270 MHz, CDCl₃) δ 9.57 (d, J=7.8 Hz, 1H), 8.10 (d, J=7.8 Hz,1H), 7.05 (t, J=7.8 Hz, 1H), 6.96 (d, J=8.1 Hz, 1H), 5.93 (bs, 1H), 5.62(bs, 1H), 4.27-4.17 (m, 3H), 2.68-2.58 (m, 5H), 2.35 (s, 6H), 1.15 (s,9H).

MS (ESI) m/z 376 (M+H)+

Anal. calcd. for C₁₉H₂₉N₅O₃: C, 60.78; H, 7.79; N, 18.65; O, 12.78.Found: C, 60.67; H. 7.89; N, 18.48.

Example 19N-[(1S)-1-(Aminocarbonyl)-2-methylpropyl]-3-[2-(dimethylamino)ethyl]-4-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described inStep 4 of Example 1 from7-methyl-1-[2-(dimethylamino)ethyl-1,3-dihydro-2H-benzimidazol-2-one(Step 1 of Example 18) and L-valinamide hydrochloride.

¹H-NMR (300 MHz, CDCl₃) δ 9.39 (d, J=8.1 Hz, 1H), 8.11 (d, J=8.1 Hz,1H), 7.06 (d, J=8.1, Hz, 1H), 6.97 (d, J=7.2 Hz, 1H), 6.12 (bs, 1H),5.50 (bs, 1H), 4.36 (dd, J=8.1, 5.1 Hz, 1H), 4.28-4.11 (m, 2H),2.65-2.56 (m, 5H), 2.49-2.37 (m, 1H), 2.34 (s, 6H), 1.08 (d, J=3.0 Hz,3H), 1.06 (d, J=3.0 Hz, 3H).

MS (ESI) m/z 362 (M+H)⁺

Anal. calcd. for C₁₈H₂₇N₆O₃(+0.7H₂O): C, 57.80; H, 7.65; N, 18.72; O,15.83. Found: C, 57.96; H, 7.71; N, 18.35.

Example 20N-{(1S)-1-{[(2-Hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl)-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamidehydrochloride

The title compound was prepared according to the procedure described inStep 4 of Example 1 from ethanolamine.

¹H-NMR (300 MHz, DMSO-d₆) δ 11.05 (bs, 1H), 9.14 (d, J=9.0 Hz, 1H), 8.30(d, J=5.4 Hz, 1H), 8.06 (d, J=7.8, Hz, 1H), 7.51 (d, J=7.8 Hz, 1H),7.30-7.17 (m, 2H), 4.42-4.37 (m, 2H), 4.32 (d, J=9.0 Hz, 1H), 3.80-3.70(m, 2H), 3.94-3.65 (m, 6H), 3.25-3.06 (m, 4H), 0.98 (s, 9H).

MS (ESI) m/z 448 (M+H)⁺

Anal. calcd. for C₂₂H₃₃N₅O₅(+1.0 H₂O, 1.0 HCl): C, 52.64; H, 7.23; N,13.95; O, 19.12; Cl, 7.06.

Found: C, 52.40; H, 7.48; N, 13.81.

Example 21N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-carboxamidehydrochloride

STEP 1.3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine

The title compound was prepared according to the procedure described inSteps 1 to 3 of Example 1 from 2-chloro-3-nitropyridine.

¹H-NMR (300 MHz, CDCl₃) δ 9.98 (bs, 1H), 8.07-8.03 (m, 1H), 7.28-7.21(m, 1H), 6.98-6.94 (m, 1H), 4.17-4.13 (m, 2H), 3.67-3.64 (m, 4H),2.83-2.79 (m, 2H), 2.60-2.57 (m, 4H).

MS (ESI) T/z 249 (M+H)⁺, 247 (M−H)⁻.

STEP 2.N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-carboxamidehydrochloride

The title compound was prepared according to the procedure described inStep 4 of Example 1 from3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine(Step 1) and L-tert-leucinamide.

¹H-NMR (300 MHz, DMSO-d₆) δ 11.40 (bs, 1H), 10.9 (bs, 1H), 8.93 (d,J=9.3 Hz, 1H), 8.22-8.14 (m, 1H), 7.72 (bs, 1H), 7.25-7.20 (m, 2H), 4.35(t, J=5.4 Hz, 2H), 4.28 (d, J=9.0 Hz, 1H), 4.05-3.90 (m, 2H), 3.88-3.50(m, 5H), 3.45-3.40 (m, 2H), 3.25-3.08 (m, 2H), 1.00 (s, 9H).

MS (ESI) m/z 405 (M+H)⁺

Anal. calcd. for C₁₉H₂₈N₆O₄(+1.0H₂O, 1.0 HCl): C, 49.72; H, 6.81; N,18.31; O, 17.43; Cl, 7.72.

Found: C, 50.05; H, 7.01; N, 18.04.

Example 22N-[(1S)-(Aminocarbonyl)-2-methylpropyl]-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamidehydrochloride

The title compound was prepared according to the procedure described inStep 4 of Example 1 from L-valinamide hydrochloride.

¹H-NMR (300 MHz, DMSO-d₆) δ 11.21 (bs, 1H), 9.00 (d, J=8.1 Hz, 1H), 8.04(d, J=8.1 Hz, 1H), 7.67 (bs, 1H), 7.50 (d, J=7.2 Hz, 1H), 7.29-7.16 (m,3H), 4.45-4.35 (m, 2H), 4.30 (dd, J=9.0, 5.1 Hz, 1H), 4.05-3.90 (m, 2H),3.85-3.66 (m, 2H), 3.65-3.51 (m, 2H), 3.50-3.40 (m, 2H), 3.25-3.05 (m,2H), 2.19-2.08 (m, 1H), 0.94 (d, J=6.6 Hz, 3H), 0.88 (d, J=6.6 Hz, 3H).

MS (ESI) m/z 390 (M+H)⁺.

Anal. calcd. for C₁₉H₂₇N₅O₄ (+0.5H₂O, 1 HCl, 0.2 C₄H₈O₂): C, 52.55; H,6.82; N, 15.48; O, 17.32, Cl, 7.83. Found: C, 52.58; H, 6.81; N, 15.15.

Example 23N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described inStep 4 of Example 1 fromN-[1S,2S)-1-(hydroxymethyl)-2-methylbutyl]amine.

MS (ESI) m/z 391 (M+H)⁺.

Rt=1.09 min

Example 24N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described inStep 4 of Example 1 fromN-[(1S)-1-hydroxymethyl)-2,2-dimethylpropyl]amine.

MS (ESI) m/z 391 (M+H)⁺.

Rt=1.67 min

Example 25N-[(1S)-(hydroxymethyl)methylbutyl]-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described inStep 4 of Example 1 from N-[(1S)-1-(hydroxymethyl)-3-methylbutyl]amine.

MS (ESI) m/z 391 (M+H)⁺.

Rt=1.76 min

Example 26N-(1-[(dimethylamino)carbonyl]-1,3-dimethylbutyl)-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described inStep 4 of Example 1 fromN-{1-[(dimethylamino)carbonyl]-1,3-dimethylbutyl}amine.

MS (ESI) m/z 446 (M+H)⁺.

Rt=1.74 min

Example 27N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-4-chloro-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

STEP 1.7-Chloro-1-(2-morpholin-4-ylethyl)-1,3-dihydro-2H-benzimidazol-2-one

The title compound was prepared according to the procedure described inSteps 1 to 3 of Example 1 from 1,2-dichloro-3-nitrobenzene.

¹H-NMR (300 MHz, DMSO-d₆) δ 11.2 (s, 1H), 7.05-6.87 (m, 3H), 4.23-4.10(m, 2H), 3.59-3.48 (m, 4H), 2.62-2.37 (m, 6H).

STEP 2.N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-4-chloro-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described inStep 4 of Example 1 from7-Chloro-1-(2-morpholin-4-ylethyl)-1,3-dihydro-2H-benzimidazol-2-one(Step 1).

¹H-NMR (300 MHz, CDCl₃) δ 9.51 (d, J=8.1 Hz, 1H), 8.18 (d, J=9.2 Hz,1H), 7.20-7.03 (m, 2H), 5.89 (bs, 1H), 5.71 (bs, 1H), 4.44-4.34 (m, 2H),4.21 (d, J=8.1 Hz, 1H), 3.70-3.60 (m, 4H), 2.83-2.44 (m, 6H), 1.14 (s,9H).

Example 28 N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-4-chloro-3(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

STEP 1.6-Chloro-1-(2-morpholin-4-ylethyl)-1,3-dihydro-2H-benzimidazol-2-one

The title compound was prepared according to the procedure described inSteps 1 to 3 of Example 1 from 4-chloro-2-flubronitrobenzene.

¹H-NMR (300 MHz, CDCl₃) δ 10.1 (s, 1H), 7.12-6.93 (m, 3H), 4.06-3.89 (m,2H), 3.79-3.60 (m, 4H), 2.79-2.47 (m, 6H).

STEP 2.N-(1S)-1-[Aminocarbonyl)-2,2-dimethylpropyl]-5-chloro-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described inStep 4 of Example 1 from6-Chloro-1-(2-morpholin-4-ylethyl)-1,3-dihydro-2H-benzimidazol-2-one(Step 1).

¹H-NMR (300 MHz, DMSO-d₆) δ 9.64 (d, J=9.2 Hz, 1H), 8.03 (d, J=8.6 Hz,1H), 7.74-7.65 (m, 2H), 7.29-7.19 (m, 2H), 4.42-4.31 (m, 2H), 4.07 (d,J=8.6 Hz, 1H), 4.08-3.94 (m, 2H), 3.82-3.07 (m, 8H), 0.99 (s, 9H).

Example 29N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-3-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

STEP 1.1-[(4-Hydroxytetrahydro-2H-pyran-4-yl)methyl]-1,3-dihydro-2H-benzimidazol-2-one

The title compound was prepared according to the procedure described inSteps 1 to 3 of Example 1 from4-{[(2-Nitrophenyl)amino]methyl}tetrahydro-2H-pyran-4-ol (WO2004029026).

¹H-NMR (300 MHz, DMSO-d₆) δ 10.9 (bs, 1H), 7.28-7.20 (m, 1H), 7.01-6.94(m, 3H), 4.76 (s, 1H), 3.73 (s, 2H), 3.66-3.51 (m, 4H), 1.69-1.35 (m,4H).

STEP 2.N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-3-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described inStep 4 of Example 1 from1-[(4-Hydroxytetrahydro-2H-pyran-4-yl)methyl]-1,3-dihydro-2H-benzimidazol-2-one(Step 1).

¹H-NMR (300 MHz, DMSO-d₆) δ 9.23 (d, J=8.8 Hz, 1H), 8.04 (d, J=7.5 Hz,1H), 7.71-7.63 (m, 1H), 7.44-7.36 (m, 1H), 7.26-7.07 (m, 3H), 4.78 (s,1H), 4.27 (d, J=9.0 Hz, 1H), 3.91-3.47 (m, 6H), 1.74-1.36 (m, 4H), 0.99(s, 9H).

Example 30N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-3-[2-(4-hydroxytetrahydro-2H-pyran-4-yl)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

STEP 1. 1,6-Dioxaspiro[2.5]octane-2-carbonitrile

To a mixture of tetrahydro-4H-pyran-4-one (5.0 g, 50 mmol) andchloroacetonitrile (3.8 g, 50 mmol) was dropwise added a solution ofpotassium tert-butoxide in tert-butanol (1.0 M, 50 mL). The reactionmixture was stirred overnight and quenched with water (100 mL). Thewhole was extracted with ethyl acetate (200 mL). The organic layer waswashed with water and brine, dried over magnesium sulfate, filtered andconcentrated in vacuo to afford the titled compound. (5.65 g)

¹H-NMR (300 MHz, CDCl₃) δ 3.94-3.79 (m, 4H), 3.35 (s, 1H), 2.17-2.03 (m,1H), 1.97-1.76 (m, 2H), 1.65-1.53 (m, 1H).

STEP 2. 4-(2-Aminoethyl)tetrahydro-2H-pyran-4-ol hydrochloride

A mixture of 1,6-dioxaspiro[2.5]octane-2-carbonitrile (3.0 g, 22 mmol)and 5% Pd on C (0.3 g) in methanol (40 mL) was stirred for 2 h. underhydrogen (3 kg/cm²). After filtration through a pad of celite, thefiltrate was concentrated in vacuo. The residue was dissolved with THF(50 mL). The solution was added dropwise to a mixture of lithiumaluminum hydride (1.6 g, 43 mmol) and THF (100 mL) and the mixture wasstirred for 2 hours at reflux temperature. After cooling to 0 degreesCelsius, Na₂SO₄-10H₂O (16 g) and KF (2.5 g) were added and the mixturewas stirred overnight. After filtration, the filtrate was concentratedin vacuo. The residue was acidified with 4N—HCl in ethyl acetate andconcentrated in vacuo. The residue was crystallized from ethanol-ether.The precipitate was filtered to afford the titled compound. (2.1 g)

¹H-NMR (300 MHz, DMSO-d₆) δ 8.19-7.78 (m, 4H), 3.81-3.35 (m, 4H),2.98-2.77 (m, 2H), 1.81-1.34 (m, 6H).

STEP 3.1-[2-(4-Hydroxytetrahydro-2H-pyran-4-yl)ethyl]-1,3-dihydro-2H-benzimidazol-2-one

The title compound was prepared according to the procedure described inSteps 1 to 3 of Example 1 from 4-(2-Aminoethyl)tetrahydro-2H-pyran-4-olhydrochloride (Step 2).

¹H-NMR (300 MHz, DMSO-d₆) δ 10.8 (bs, 1H), 7.14-6.91 (m, 4H), 4.57 (s,1H), 3.95-3.81 (m, 2H,), 3.70-3.44 (m, 4H), 1.75-1.42 (m, 6H).

STEP 4.N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-3-[2-(4-hydroxytetrahydro-2H-pyran-4-yl)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described inStep 4 of Example 1 from1-[2-(4-Hydroxytetrahydro-2H-pyran-4-yl)ethyl]-1,3-dihydro-2H-benzimidazol-2-one(Step 3).

¹H-NMR (300 MHz, DMSO-d₆) δ 9.23 (d, J=9.2 Hz, 1H). 8.05 (d, J=7.9 Hz,1H), 7.72-7.64 (m, 1H), 7.35-7.12 (m, 4H), 4.61 (s, 1H), 4.26 (d, Jo-9.2Hz, 1H), 4.08-3.91 (m, 2H), 3.75-3.47 (m, 4H), 1.87-1.44 (m, 4H), 1.00(s, 9H).

Example 31N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-3-[2-(ethylthio)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

STEP 1. 1-[2-(Ethylthio)ethyl]-1,3-dihydro-2H-benzimidazol-2-one

The title compound was prepared according to the procedure described inSteps 1 to 3 of Example 1 from 2-(ethylthio)ethanamine hydrochloride.

¹H-NMR (300 MHz, CDCl₃) δ 8.97 (bs, 1H), 7.17-6.96 (m, 4H), 4.14-4.02(m, 2H), 2.95-2.84 (m, 2H), 1.69-1.35 (m, 4H), 2.63 (q, J=7.3 Hz, 2H),1.28 (t, J=7.3 Hz, 3H)

STEP 2.N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-3-[2-(ethylthio)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described inStep 4 of Example 1 from1-[2-(Ethylthio)ethyl]-1,3-dihydro-2H-benzimidazol-2-one (Step 1).

¹H-NMR (300 MHz, DMSO-d₆) δ 9.20 (d, J=8.8 Hz, 1H), 8.05 (d, J=7.9 Hz,1H), 7.73-7.65 (m, 1H), 7.42-7.11 (m, 4H), 4.27 (d, J=8.8 Hz, 1H),4.15-4.04 (m, 2H), 2.95-2.83 (m, 2H), 2.65-2.54 (m, 2H), 1.21-1.13 (m,3H), 0.99 (s, 9H).

Example 32N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-3-[2-(methylthio)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

STEP 1. 1-[2-(Methylthio)ethyl]-1,3-dihydro-2H-benzimidazol-2-one

The title compound was prepared according to the procedure described inSteps 1 to 3 of Example 1 from 2-(methylthio)ethanamine.

¹H-NMR (300 MHz, CDCl3) δ 9.36 (bs, 1H), 7.17-6.99 (m, 4H), 4.18-4.04(m, 2H), 2.94-2.81 (m, 2H), 2.20 (s, 3H).

STEP 2.N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-3-[2-(methylthio)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described inStep 4 of Example 1 from1-[2-(Methylthio)ethyl]-1,3-dihydro-2H-benzimidazol-2-one (Step 1).

H-NMR (300 MHz, DMSO-d₆) δ 9.19 (d, J=9.2 Hz, 1H), 8.06 (d, J=7.9 Hz,1H), 7.72-7.64 (m, 1H), 7.42-7.12 (m, 4H), 4.27 (d, J=8.6 Hz, 1H),4.17-4.06 (m, 2H), 2.90-2.81 (m, 2H), 2.14 (s, 3H), 1.00 (s, 9H).

Example 33

N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[2-(methylsulfinyl)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

A mixture ofN-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[2-methylthio)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide(Example 32, 150 mg), m-chloroperbenzoic acid (70%, 170 mg) and NaHCO3(150 mg) in dichloromethane (5 mL) was stirred overnight and quenchedwith sat. Na₂S₂O₃ aq. (25 mL) The whole was extracted with ethyl acetate(25 mL×2). The combined organic layers were washed with brine, driedover magnesium sulfate, filtrated and concentrated in vacuo. The residuewas purified by preparative TLC to yield the titled compound. (180 mg)

¹H-NMR (300 MHz, CDCl3) δ 9.39-9.29 (m, 1H), 8.12 (d, J=7.9 Hz, 1H),7.31-7.11 (m, 3H), 6.46-6.36 (m, 1H), 6.19-6.07 (m, 1H), 4.43-4.32 (m,2H), 4.28 (d, J=8.6 Hz, 1H), 3.33-2.99 (m, 2H), 2.67 (s, 3H), 1.13 (s,9H).

Example 34

N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-3-[2-(methylsulfonyl)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

mixture ofN-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[2-(methylsulfinyl)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide(Example 33, 150 mg), m-chloroperbenzoic acid (70%, 170 mg) and NaHCO₃(150 mg) in dichloromethane (5 mL) was stirred overnight and quenchedwith sat. Na2S2O3 aq. (25 mL) The whole was extracted with ethyl acetate(25 mL×2). The combined organic layers were washed with brine, driedover magnesium sulfate, filtrated and concentrated in vacuo. The residuewas purified by preparative TLC to yield the titled compound. (100 mg)

¹H-NMR (300 MHz, DMSO-d₆) δ 9.14 (d, J=8.6 Hz, 1H), 8.06 (d, J=7.9 Hz,1H), 7.74-7.65 (m, 1H), 7.43-7.15 (m, 4H), 4.40-4.24 (m, 3H), 3.72-3.53(m, 2H), 3.11 (s, 3H), 1.00 (s, 9H).

Following Examples 35 to 90 were prepared according to the proceduredescribed in Step 4 of Example 1.

Example 35 MethylN-{[3-(2-Morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}-L-phenylalaninate

¹H-NMR (300 MHz, CDCl₃) δ 9.25 (d, J = 7.5 Hz, 1 H), 8.17-8.14 (m, 1 H),7.33-7.12 (m, 7 H), 7.03-7.00 (m, 1 H), 4.89 (dt, J = 7.5, 5.7 Hz, 1 H),4.04-3.94 (m, 2 H), 3.74 (s, 3 H), 3.66 (t, J = 4.8 Hz, 4 H), 3.28 (dd,J = 13.8, 5.4 Hz, 1 H), 3.15 (dd, J = 13.8, 7.5 Hz, 1 H), 2.72-2.62 (m,2 H), 2.57-2.47 (m, 4 H). MS (ESI) m/z 453 (M + H)⁺. Example 36N-(3,4-Dihydro-2H-chromen-4-yl)-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide hydrochloride

¹H-NMR (300 MHz, CDCl₃) δ 13.81 (bs, 1 H), 8.87 (d, J = 7.5 Hz, 1 H),8.24 (d, J = 7.5 Hz, 1 H), 7.57 (d, J = 7.5 Hz, 1 H), 7.34-7.18 (m, 4H), 6.95-6.85 (m, 2 H), 5.26-5.20 (m, 1 H), 4.65-4.50 (m, 2 H),4.37-3.92 (m, 6 H), 3.57-3.40 (m, 2 H), 3.35-3.22 (m, 2 H), 3.10-2.85(m, 2 H), 2.40-2.30 (m, 1 H), 2.23-2.14 (m, 1 H). MS (ESI) m/z 423 (M +H)⁺. Anal. calcd. for C₂₃H₂₆N₄O₄ (+0.6 H₂O, 1 HCl): C, 58.81; H, 6.05;N, 11.93; O, 15.67, Cl, 7.75. Found: C, 59.13; H, 6.23; N; 11.53. IR(KBr)ν_(max) 1728, 1537, 1489, 1385 cm⁻¹. Example 37N-cyclohexyl-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 373 (M + H)⁺. Rt = 1.96 min Example 38N-(2-methylcyclohexyl)-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 387 (M + H)⁺. Rt = 1.24 min Example 39N-(2,3-dihydro-1H-inden-1-yl)-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 407 (M + H)⁺. Rt = 1.22 min Example 40N-(2,3-dimethylcyclohexyl)-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 401 (M + H)⁺. Rt = 1.32 min Example 413-(2-morpholin-4-ylethyl)-2-oxo-N-(3,3,5-trimethylcyclohexyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 415 (M + H)⁺. Rt = 1.37 min Example 42N-(4-methylcyclohexyl)-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 387 (M + H)⁺. Rt = 1.26 min Example 43N-(1,3-dimethylbutyl)-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 375 (M + H)⁺. Rt = 1.24 min Example 44N-(1-methylpentyl)-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 375 (M + H)⁺. Rt = 1.24 min Example 453-(2-morpholin-4-ylethyl)-2-oxo-N-[(1R)-1,2,2-trimethylpropyl]-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 375 (M + H)⁺. Rt = 1.21 min Example 46N-cyclooctyl-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 401 (M + H)⁺. Rt = 1.31 min Example 47N-(1-methyl-1-phenylethyl)-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 409 (M + H)⁺. Rt = 1.21 min Example 48N-[(1R)-1,2-dimethylpropyl]-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 361 (M + H)⁺. Rt = 1.17 min Example 49N-[(1S)-2,3-dihydro-1H-inden-1-yl]-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihdyro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 407 (M + H)⁺. Rt = 1.22 min Example 50N-[(1S)-1-cyclohexylethyl]-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 401 (M + H)⁺. Rt = 1.32 min Example 513-(2-morpholin-4-ylethyl)-2-oxo-N-(1-propylbutyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 389 (M + H)⁺. Rt = 1.29 min Example 52N-[(1R)-1-cyclohexylethyl]-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 401 (M + H)⁺. Rt = 1.32 min Example 533-(2-morpholin-4-ylethyl)-2-oxo-N-[(1S)-1,2,2-trimethylpropyl]-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 375 (M + H)⁺. Rt = 1.21 min Example 54N-[(3S,5S,7S)-1-adamantyl]-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 425 (M + H)⁺. Rt = 1.22 min Example 55N-(1-ethynylcyclohexyl)-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihdyro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 397 (M + H)⁺. Rt = 1.20 min Example 563-(2-morpholin-4-ylethyl)-2-oxo-N-[(1S,2R,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 427 (M + H)⁺. Rt = 1.38 min Example 57N-(dicyclopropylmethyl)-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 385 (M + H)⁺. Rt = 1.20 min Example 58N-(2-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 437 (M + H)⁺. Rt = 1.13 min Example 59 methylN-{[3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-yl]carbonyl}-L-leucinate

MS (ESI) m/z 419 (M + H)⁺. Rt = 1.18 min Example 60N-[1-(1-adamantyl)ethyl]-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 453 (M + H)⁺. Rt = 1.44 min Example 61N-(1,1-diethylprop-2-yn-1-yl)-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 385 (M + H)⁺. Rt = 1.21 min Example 62N-{[(1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]methyl}-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 427 (M + H)⁺. Rt = 1.38 min Example 633-(2-morpholin-4-ylethyl)-2-oxo-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 421 (M + H)⁺. Rt = 2.16 min Example 64 ethyl(1R,2S)-2-({[3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-yl]carbonyl}amino)cyclohexanecarboxylate

MS (ESI) m/z 445 (M + H)⁺. Rt = 1.98 min Example 65 methyl1-({[3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}amino)cyclohexanecarboxylate

MS (ESI) m/z 431 (M + H)⁺. Rt = 1.88 min Example 663-(2-morpholin-4-ylethyl)-2-oxo-N-[(1R,2R)-2-(phenylthio)cyclopentyl]-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 467 (M + H)⁺. Rt = 2.25 min Example 67N-(1-ethyl-1-methylpropyl)-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 375 (M + H)⁺. Rt = 1.36 min Example 68N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 385 (M + H)⁺. Rt = 2.02 min Example 693-(2-morpholin-4-ylethyl)-2-oxo-N-(3,3,5,5-tetramethylcyclohexyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 429 (M + H)⁺. Rt = 2.48 min Example 703-(2-morpholin-4-ylethyl)-2-oxo-N-(1,1,3,3-tetramethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 303 (M + H)⁺. Rt = 2.35 min Example 71N-(1-isopropyl-2-methylpropyl)-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 389 (M + H)⁺. Rt = 1.36 min Example 72N-[(1S,4R)-bicyclo[2.2.1]hept-2-yl]-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 385 (M + H)⁺. Rt = 2.00 min Example 733-(2-morpholin-4-ylethyl)-N-1-naphthyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, CDCl₃). δ 11.50 (bs, 1 H), 8.37-8.34 (m, 1 H), 8.26 (d,J = 7.5 Hz, 1 H), 8.16 (d, J = 8.4 Hz, 1 H), 7.91-7.89 (m, 1 H), 7.71(d, J = 8.3 Hz, 1 H), 7.63-7.51 (m, 3 H), 7.30-7.22 (m, 2 H), 7.13-7.10(m, 1 H), 4.12 (t, J = 6.6 Hz, 2 H), 3.72-3.68 (m, 4 H), 2.77 (t, J =6.6 Hz, 2 H), 2.57-2.60 (m, 4 H). MS (ESI) m/z 417.2 (M + H)⁺. Anal.calcd. for C₂₄H₂₄N₄O₃: C, 69.21; H, 5.81; N, 13.45; O, 11.52. Found: C,69.35; H, 5.84; N; 13.49. IR (KBr)ν_(max) 2849, 1730, 1690, 1564, 1489,1385 cm⁻¹. mp 137.3, 128.3 degrees Celsius. Example 743-(2-morpholin-4-ylethyl)-2-oxo-N-(5,6,7,8-tetrahydonaphthalen-1-yl)-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, CDCl₃). δ 10.69 (bs, 1 H), 8.34-8.31 (m, 1 H), 7.93 (d,J = 8.0 Hz, 1 H), 7.27-7.15 (m, 3 H), 7.09-7.06 (m, 1 H), 6.93 (d, J =7.7 Hz, 1 H), 4.06 (t, J = 6.8 Hz, 2 H), 3.69-3.66 (m, 4 H), 2.83-2.70(m, 6 H), 2.57-2.54 (m, 4 H), 1.94-1.86 (m, 2 H), 1.82-1.74 (m, 2 H). MS(ESI) m/z 421.2 (M + H)⁺. Anal. calcd. for C₂₄H₂₈N₄O₃: C, 68.55; H,6.71; N, 13.32; O, 11.41. Found: C, 68.34; H, 6.73; N; 13.12. IR(KBr)ν_(max) 2945, 1732, 1609, 1568, 1387, 1302, 1159, 1117 cm⁻¹. mp141.5 degrees Celsius. Example 75N-(1-adamantylmethyl)-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, CDCl₃). δ 8.86-8.82 (m, 1 H), 8.26-8.23 (m, 1 H),7.24-7.14 (m, 2 H), 7.05-7.02 (m, 1 H), 4.02 (t, J = 6.8 Hz, 2 H),3.69-3.66 (m, 4 H), 3.13 (d, J = 6.0 Hz, 2 H), 2.70 (t, J = 6.8 Hz, 2H), 2.55-2.52 (m, 4 H), 2.00 (bs, 3 H), 1.75-1.63 (m, 6 H), 1.59-1.58(m, 6 H). MS (ESI) m/z 439.3 (M + H)⁺. Anal. calcd. for C₂₅H₃₄N₄O₃: C,68.47; H, 7.81; N, 12.78; O, 10.94. Found: C, 68.66; H, 7.82; N; 12.69.IR (KBr)ν_(max) 2907, 1730, 1558, 1393 cm⁻¹. mp 142.0 degrees Celsius.Example 763-(2-morpholin-4-ylethyl)-2-oxo-N-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-2,3-dihydro-1H-benzimidazole-1-carboxamide hydrochloride

¹H-NMR (300 MHz, CDCl₃). δ 13.86 (bs, 1 H), 8.82 (d, J = 8.4 Hz, 1 H),8.27 (dd, J = 8.1, 1.5 Hz, 1 H), 7.58-7.55 (m, 1 H), 7.41-7.36 (m, 1 H),7.32-7.11 (m, 4 H), 5.29-5.23 (m, 1 H), 4.61-4.57 (m, 2 H), 4.28-4.20(m, 2 H), 3.99 (d, J = 11.7 Hz, 2 H), 3.49-3.45 (m, 2 H), 3.30-3.25 (m,2 H), 2.93-2.75 (m, 4 H), 2.22-2.12 (m, 1 H), 2.03-1.87 (m, 3 H). MS(ESI) m/z 421.3(M + H)⁺. Anal. calcd. for C₂₄H₂₈N₄O₃ (+0.4 H₂O, 1.0HCl): C, 62.10; H, 6.47; N, 12.07; O, 11.72, Cl, 7.64. Found: C, 62.42;H, 6.56; N; 11.75. Example 773-(2-morpholin-4-ylethyl)-2-oxo-N-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]-2,3-dihydro-1H-benzimidazole-1-carboxamide hydrochloride

¹H-NMR (300 MHz, CDCl₃). δ 13.90 (bs, 1 H), 8.82 (d, J = 8.1 Hz, 1 H),8.27 (dd, J = 8.1, 1.2 Hz, 1 H), 7.59-7.56 (m, 1 H), 7.41-7.36 (m, 1 H),7.32-7.11 (m, 4 H), 5.29-5.23 (m, 1 H), 4.62-4.57 (m, 2 H), 4.29-4.21(m, 2 H), 4.01-3.98 (m, 2 H), 3.49-3.45 (m, 2 H), 3.30-3.25 (m, 2 H),2.93-2.75 (m, 4 H), 2.22-2.12 (m, 1 H), 2.03-1.87 (m, 3 H). MS (ESI) m/z421.3 (M + H)⁺. Anal. calcd. for C₂₄H₂₈N₄O₃ (+0.2 H₂O, 1.0 HCl): C,62.59; H, 6.43; N, 12.16; O, 11.12, Cl, 7.70. Found: C, 62.36; H, 6.59;N; 11.80. Example 78N-isoquinolin-1-yl-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, CDCl₃). δ 11.97 (s, 1 H), 8.47 (d, J = 5.7 Hz, 1 H),8.44-8.39 (m, 1 H), 8.23 (d, J = 8.7 Hz, 1 H), 7.88-7.85 (m, 1 H),7.76-7.65 (m, 2 H), 7.53 (d, J = 5.7 Hz, 1 H), 7.31-7.21 (m, 2 H),7.14-7.09 (m, 1 H), 4.12 (t, J = 6.6 Hz, 2 H), 3.71-3.68 (m, 4 H), 2.77(t, J = 6.6 Hz, 2 H), 2.60-2.57 (m, 4 H). MS (ESI) m/z 418.3 (M + H)⁺.Anal. calcd. for C₂₄H₂₃N₅O₃: C, 66.17; H, 5.55; N, 16.78; O, 11.50.Found: C, 66.13; H, 5.56; N; 16.62. IR (KBr)ν_(max) 2827, 1753, 1634,1547, 1377 cm⁻¹. mp 139.0 degress Celsius. Example 79 MethylN-{[4-methoxy-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}-3-methyl-L-valinate

¹H-NMR (300 MHz, CDCl₃) δ 9.54 (d, J = 8.4 Hz, 1 H), 7.86 (dd, J = 8.1,0.6 Hz, 1 H), 7.08 (t, J = 8.1 Hz, 1 H), 6.76 (d, J = 8.1 Hz, 1 H), 4.43(d, J = 8.4 Hz, 1 H), 4.31-4.17 (m, 2 H), 3.91 (s, 3 H), 3.76 (s, 3 H),3.67 (t, J = 4.5 Hz, 4 H), 2.75-2.64 (m, 2 H), 2.59-2.50 (m, 4 H), 1.09(s, 9 H), MS (ESI) m/z 449 (M + H)⁺. Anal. calcd. for C₂₂H₃₂N₄O₆: C,58.91; H, 7.19; N, 12.49; O, 21.40. Found: C, 58.78; H, 7.12 N; 12.35.Example 80N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-4-methoxy-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, CDCl3) δ 9.58 (d, J = 7.8 Hz, 1 H), 7.84 (dd, J = 8.4,0.9 Hz, 1 H), 7.08 (d, J = 8.4 Hz, 1 H), 6.77 (d, J = 8.4 Hz, 2 H), 5.96(bs, 1 H), 5.66 (bs, 1 H), 4.32-4.15 (m, 3 H), 3.91 (s, 3 H), 3.67 (t, J= 4.5 Hz, 2 H), 2.76-2.62 (m, 2 H), 2.60-2.49 (m, 4 H), 1.14 (s, 9 H).MS (ESI) m/z 434.4 (M + H)⁺. Anal. calcd. for C₂₁H₃₁N₅O₅ (+1 H₂O): C,57.94; H, 7.22; N, 16.09; O, 18.74. Found: C, 57.77; H, 7.19; N; 15.72.mp 210.9 degrees Celsius Example 81N-[(1S)-1-(Aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-(2-piperidin-1-ylethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide hydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ 10.51 (bs, 1 H), 9.13 (d, J = 9.0 Hz, 1 H),8.06 (dd, J = 7.8, 0.9 Hz, 1 H), 7.70 (bs, 1 H), 7.53 (d, J = 7.8 Hz, 1H), 7.31-7.16 (m, 3 H), 4.35-4.45 (m, 2 H), 4.27 (d, J = 9.0 Hz, 1 H),3.70-3.51 (m, 2 H), 3.43-3.31 (m, 2 H), 3.05-2.87 (m, 2 H), 1.88-1.65(m, 5 H), 1.47-1.30 (m, 1 H), 1.00 (s, 9 H). MS (ESI) m/z 4.02.3 (M +H)⁺. Anal. calcd. for C₂₁H₃₁N₅O₃ (+1.0 H₂O, 1.0 HCl): C, 55.32; H, 7.52;N, 15.36; O, 14.04; Cl, 7.78. Found: C, 55.70; H, 7.69; N; 15.30.Example 82N-{(1S,2S)-1-[(dimethylamino)carbonyl]-2-methylbutyl}-2-oxo-3-(2-piperidin-1-ylethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide

MS (ESI) m/z 430 (M + H)⁺. Rt = 1.07 min Example 83N-{(1S,2S)-1-[(dimethylamino)carbonyl]-2-methylbutyl}-2-oxo-3-(2-thiomorpholin-4-ylethyl)-2,3-dihydro-1H-benzimidazol-1-carboxamide

MS (ESI) m/z 448 (M + H)⁺. Rt = 1.06 min Example 844-methoxy-3-(2-morpholin-4-ylethyl)-N-1-naphthyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, CDCl₃). δ 11.64 (bs, 1 H), 8.25 (dd, J = 7.5, 0.9 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1 H), 8.03 (dd, J = 8.25, 0.9 Hz, 1 H),7.90-7.88 (m, 1 H), 7.70 (d, J = 8.4 Hz, 1 H), 7.63-7.50 (m, 3 H), 7.16(t, J = 8.3 Hz, 1 H), 6.83-6.81 (m, 1 H), 4.34 (t, J = 6.8 Hz, 2 H),3.94 (s, 3 H), 3.71-3.68 (m, 4 H), 2.75 (t, J = 6.8 Hz, 2 H), 2.60-2.57(m, 4 H). MS (ESI) m/z 447.2 (M + H)⁺. Anal. calcd. for C₂₅H₂₆N₄O₄: C,67.25; H, 5.87; N, 12.55; O, 14.33. Found: C, 67.30; H, 6.01; N; 12.48.IR (KBr)ν_(max) 2959, 1734, 1690, 1572, 1387, 1234 cm⁻¹. mp 170.9degrees Celsius. Example 85N-1-naphthyl-2-oxo-3-(2-piperidin-1-ylethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, CDCl₃). δ 11.53 (bs, 1 H), 8.36-8.33 (m, 1 H), 8.26(dd, J = 7.5, 0.9 Hz, 1 H), 8.17 (d, J = 8.7 Hz, 1 H), 7.91-7.88 (m, 1H), 7.70 (d, J = 8.1 Hz, 1 H), 7.63-7.51 (m, 3 H), 7.30-7.20 (m, 2 H),7.16-7.13 (m, 1 H), 4.16-4.07 (m, 2 H), 2.77-2.67 (m, 2 H), 2.58-2.46(m, 4 H), 1.65-1.52 (m, 4 H), 1.50-1.39 (m, 2 H). MS (ESI) m/z 415.3(M + H)⁺. Anal. calcd. for C₂₅H₂₆N₄O₂: C, 72.44; H, 6.32; N, 13.52; O,7.72. Found C, 72.51; H, 6.41; N; 13.26. IR (KBr)ν_(max) 2941, 1734,1572, 1379, 1261, 1163 cm⁻¹. mp 145.7 degrees Celsius. Example 863-(2-morpholin-4-ylethyl)-2-oxo-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-carboxamide hydrochloride

¹H-NMR (300 MHz, CDCl₃). δ 13.59 (bs, 1 H), 8.57-8.52 (m, 2 H), 8.13 (d,J = 4.8 Hz, 1 H), 7.45-7.42 (m, 1 H), 7.29-7.12 (m, 3 H), 5.27-5.20 (m,1 H), 4.63 (bs, 2 H), 4.32-4.22 (m, 2 H), 3.98-3.93 (m, 2 H), 3.74-3.70(m, 2 H), 3.53 (bs, 2 H), 2.94-2.75 (m, 4 H), 2.25-2.15 (m, 1 H),2.01-1.89 (m, 3 H). MS (ESI) m/z 422.2 (M + H)⁺. Anal. calcd. forC₂₃H₂₇N₅O₂ (+2.0 HCl): C, 55.87; H, 5.91; N, 14.17; O, 9.71; Cl, 14.34.Found: C, 55.87; H, 5.99; N; 14.23. IR (KBr)ν_(max) 1736, 1535, 1394cm⁻¹. Example 874-methyl-3-(2-morpholin-4-ylethyl)-2-oxo-N-(1,2,3,4-tetrahydronaphthalen-1-yl),2,3-dihydro-1H-benzimidazole-1-carboxamide hydrochloride

¹H-NMR (300 MHz, CDCl₃). δ 14.98 (bs, 1 H), 8.94-8.92 (m, 1 H), 8.23 (d,J = 8.1 Hz, 1 H), 7.40-7.37 (m, 1 H), 7.21-7.17 (m, 2 H), 7.15-7.10 (m,2 H), 7.01 (d, J = 7.2 Hz, 1 H), 5.29-5.23 (m, 1 H), 4.80-4.68 (m, 2 H),4.34-4.26 (m, 2 H), 4.01-3.97 (m, 2 H), 3.60-3.48 (m, 2 H), 3.30-3.15(m, 2 H), 3.05-2.90 (m, 2 H), 2.88-2.81 (m, 1 H), 2.72 (s, 3 H),2.19-2.13 (m, 1 H), 2.02-1.89 (m, 4 H). MS (ESI) m/z 435.1 (M + H)⁺.Anal. calcd. for C₂₅H₃₀N₄O₃ (+1.0 HCl): C, 63.75; H, 6.63; N, 11.90; O,10.19; Cl, 7.53. Found: C, 63.42; H, 6.64; N; 11.79. IR (KBr)ν_(max)1724, 1537, 1452 cm⁻¹. Example 883-(2-methoxyethyl)-2-oxo-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, CDCl₃). δ 9.07 (d, J = 7.5 Hz, 1 H), 8.29-8.26 (m, 1H), 7.43-7.40 (m, 1 H), 7.28-7.10 (m, 6 H), 5.30-5.24 (m, 1 H), 4.03 (t,J = 5.4 Hz, 2 H), 3.66 (t, J = 5.4 Hz, 2 H), 3.32 (s, 3 H), 2.93-2.74(m, 2 H), 2.21-2.11 (m, 1 H), 2.05-1.87 (m, 3 H). MS (ESI) m/z 366.1(M + H)⁺. Anal. calcd. for C₂₁H₂₃N₃O₃: C, 69.02; H, 6.34; N, 11.50; O,13.13. Found: C, 69.08; H, 6.52; N; 11.51. IR (KBr)ν_(max) 1726, 1520,1383, 1171 cm⁻¹. mp 115.6 degrees Celsius. Example 892-oxo-3-(2-pyrrolidin-1-ylethyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-2,3-dihydro-1H-benzimidazole-1-carboxamidehydrochloride

¹H-NMR (300 MHz, CDCl₃). δ 13.19 (bs, 1 H), 8.84 (d, J = 8.4 Hz, 1 H),8.27 (dd, J = 7.8, 0.9 Hz, 1 H), 7.58 (d, J = 7.2 Hz, 1 H), 7.41-7.38(m, 1 H), 7.32-7.11 (m, 4 H), 5.29-5.23 (m, 1 H), 4.55-4.51 (m, 2 H),3.78 (bs, 2 H), 3.89 (t, J = 7.2 Hz, 2 H), 2.91-2.77 (m, 4 H), 2.21-2.13(m, 4 H), 2.03-1.71 (m, 4 H). MS (ESI) m/z 405.2 (M + H)⁺. Anal. calcd.for C₂₄H₂₈N₄O₂ (+1.0 HCl, 0.3 H₂O): C, 64.58; H, 6.68; N, 12.55; O,8.24; Cl, 7.94. Found: C, 64.67; H, 7.08; N; 12.56. IR (KBr)ν_(max)1728, 1533, 1489, 1383 cm⁻¹. mp 165.6 degrees Celsius. Example 903-[(1-Methylpiperidin-2-yl)methyl]-N-1-naphthyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide hydrochloride

¹H-NMR (300 MHz, CDCl₃). δ 12.98 (bs, 1 H), 11.24 (s, 1 H), 8.33 (dd, J= 7.8, 0.9 Hz, 1 H), 8.25 (dd, J = 7.8, 0.9 Hz, 1 H), 8.11 (d, J = 8.7Hz, 1 H), 7.92-7.89 (m, 1 H), 7.73 (d, J = 8.1 Hz, 1 H), 7.63-7.52 (m, 4H), 7.37-7.24 (m, 2 H), 4.72 (dd J = 14.7, 5.1 Hz, 1 H), 4.60-4.52 (m, 1H), 3.57-3.45 (m, 2 H), 2.97 (s, 3 H), 2.90-2.81 (m, 1 H), 2.33-2.21 (m,2 H), 2.01-1.86 (m, 3 H), 1.51-1.43 (m, 1 H). MS (ESI) m/z 415.1 (M +H)⁺. Anal. calcd. for C₂₅H₂₆N₄O₂ (+0.7 H₂O, 1.0 HCl, 0.2 C₄H₈O₂) C,64.40; H, 6.28; N, 11.64; O, 10.31; Cl, 7.37. Found: C, 64.56; H, 6.06;N; 11.32. IR (KBr)ν_(max) 1740, 1570, 1383 cm⁻¹.

Following Examples 91 to 92 were prepared according to the proceduredescribed in Example 3.

Example 91 N-[(1S,2S)-2-Methyl-1-(morpholin-4-ylcarbonyl)butyl]-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamlde hydrochloride

¹H-NMR (270 MHz, CDCl₃) δ 9.23 (d, J = 8.9 Hz, lH), 8.15 (d, J = 7.8 Hz,1H), 7.60-7.48 (m, 1H), 7.31-7.17 (m, 2H), 4.87 (dd, J = 8.37, 6.21 Hz,1H), 4.76-4.45 (m, 2H), 4.35-3.95 (m, 4H), 3.80-3.25 (m, 12H), 3.07-2.87(m, 2H), 1.92-1.83 (m, 1H), 1.70-1.55 (m, 1H), 1.28-1.17 (m, 1H), 1.04(d, J = 6.75 Hz, 3H), 0.94 (t, J = 7.3 Hz, 3H). MS (ESI) m/z 474 (M +H)⁺. Anal. calcd. for C₂₄H₃₅N₅O₅ (+1 H₂O, 1 HCl): C, 54.59; H, 7.25; N,13.26; O, 18.18, Cl, 6.71. Found: C, 54.52; H, 7.16; N; 12.86. Example92N-[(1S)-2,2-Dimethyl-1-(pyrrolidin-1-ylcarbonyl)propyl]-3-{2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide hydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ 11.46 (bs, 1H), 9.18 (d, J = 9.0 Hz, 1H),8.05 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.34-7.17 (m, 2H),4.60 (d, J = 9.0 Hz, 1H), 4.40 (t, J = 6.3 Hz, 2H), 4.06-3.98 (m, 2H),3.84-3.72 (m, 2H), 3.70-3.28 (m, 12H), 3.26-3.15 (m, 2H), 1.95-1.87 (m,2H), 1.83-1.75 (m, 2H), 1.02 (s, 9H). MS (ESI) m/z 458 (M + H)⁺. Anal.calcd. for C₂₄H₃₅N₅O₄ (+1 H₂O, 1 HCl): C, 56.30; H, 7.48; N, 13.68; O,15.62, Cl, 6.92. Found: C, 56.53; H, 7.60; N; 13.35.

Example 93N-[(1S)-2,2-dimethyl-(2-methyl-2H-tetrazol-5-yl)propyl]-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

STEP 1. benzyl [(1S)-2,2-dimethyl-1-(2H-tetrazol-5-yl)propyl]carbamate

The title compound was prepared according to the procedure described inthe literature (Demko. Z. P.; Sharpless, K. B. Org. Lett. 2002, 4,2525-2527.) from benzyl[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]carbamate (Step 1 of Example4).

MS (ESI) m/z 290 (M+H)⁺, 288 (M−H)⁻.

STEP 2. benzyl [(1S)-2,2-dimethyl-1-(2-methyl-2H-tetrazol-5-yl)propyl]carbamate and benzyl[(1S)-2,2-dimethyl-1-(1-methyl-1H-tetrazol-5-yl)propyl]carbamate

To a suspension of benzyl[(1S)-2,2-dimethyl-1-(2H-tetrazol-5-yl)propyl]carbamate (280 mg, 0.96mmol), potassium carbonate (660 mg, 4.8 mmol) and methyl iodide (0.24mL, 3.8 mmol) in acetone (5 mL) was stirred at 0 degrees Celsius for 10minutes and warmed to room temperature. After 4 hours, the mixture wasfiltered and concentrated. The residue was purified by columnchromatography on silica gel eluting with hexane/ethyl acetate(8/1-4/1-1/1) to afford 166 mg (57%) of benzyl[(1S)-2,2-dimethyl-1-(2-methyl-2H-tetrazol-5-yl)propyl]carbamate and 82mg (28%) of benzyl[(1S)-2,2-dimethyl-1-(1-methyl-1H-tetrazol-5-yl)propyl]carbamate.

benzyl [(1S)-2,2-dimethyl-1,2-methyl-2H-tetrazol-5-yl)propyl]carbamate

¹H-NMR (300 MHz, CDCl₃) δ 7.40-7.28 (m, 5H), 5.59 (d, J=9.3 Hz, 1H),5.12 (d, J=12.3 Hz, 1H), 5.06 (d, J=12.3 Hz, 1H), 5.00 (d, J=9.3 Hz,1H), 4.32 (s, 3H), 0.97 (s, 9H).

MS (ESI) m/z 304 (M+H)⁺.

benzyl [(1S)-2,2-dimethyl-1-(1-methyl-1H-tetrazol-5-yl)propyl]carbamate

¹H-NMR (300 MHz, CDCl₃) δ 7.40-7.28 (m, 5H), 5.55 (d, J=9.6 Hz, 1H),5.10 (d, J=12.6 Hz, 1H), 5.02 (d, J=12.6 Hz, 1H), 4.84 (d, J=9.6 Hz,1H), 4.13 (s, 3H), 1.05 (s, 9H).

MS (ESI) m/z 304 (M+H)⁺.

STEP 3.N-[(1S)-2,2-dimethyl-1-(2-methyl-2H-tetrazol-5-yl)propyl]-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

The titled compound was prepared according to the procedure described inStep 4 of example 1 from(1S)-2,2-dimethyl-1-(2-methyl-2H-tetrazol-5-yl)propan-1-amine which wasprepared from benzyl[(1S)-2,2-dimethyl-1-(2-methyl-2H-tetrazol-5-yl)propyl]carbamateaccording to the procedure described in step 2 of example 4.

¹H-NMR (300 MHz, CDCl₃) δ 13.9 (bs, 1H), 9.55-9.32 (m, 1H), 8.22-8.01(m, 1H), 7.68-7.43 (m, 1H), 7.35-7.05 (m, 1H), 5.24-5.15 (m, 1H),4.78-4.47 (m, 2H), 4.40-3.85 (m, 7H), 3.62-3.18 (m, 4H), 3.12-2.80 (m,2H), 1.08 (s, 9H).

MS (ESI) m/z 443 (M+H)⁺.

Anal. calcd. for C₂₁H₃₀N₈O₃ (+0.5H₂O, 1.0 HCl, 0.5 C₄H₈O₂): C, 51.92; H,6.82; N, 21.06; O, 13.53; Cl, 6.66. Found: C, 51.73; H, 6.79; N, 21.20.

Example 94N-[(1S)-2,2-dimethyl-1-(1-methyl-1H-tetrazol-6-yl)propyl]-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

The titled compound was prepared according to the procedure described inStep 2 of Example 12 from(1S)-2,2-dimethyl-1-(1-methyl-1H-tetrazol-5-yl)propan-1-amine which wasprepared from benzyl[(1S)-2,2-dimethyl-1-(1-methyl-1H-tetrazol-5-yl)propyl]carbamateaccording to the procedure described in Step 2 of Example 4.

¹H-NMR (300 MHz, CDCl₃) δ 9.72 (d, J=8.1 Hz, 1H), 8.06 (d, J=7.2 Hz,1H), 7.23-7.00 (m, 4H), 5.09 (d, J=8.1 Hz, 1H), 4.22 (s, 3H), 4.07-3.95(m, 2H), 3.73-3.61 (m, 4H), 2.75-2.44 (m, 6H), 1.17 (s, 9H).

MS (ESI) m/z 443 (M+H)⁺.

Example 95N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(2-methyl-2-methylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

STEP 1. 2-methoxy-2-methylpropan-1-amine

To a suspension of lithium aluminum hydride (2.1 g, 55 mmol) and diethylether (30 mL) at 0 degrees Celsius was added a solution of2-methoxy-2-methylpropanenitrile (prepared from 2.5 g (29 mmol) of2-hydroxy-2-methylpropanenitrile according to the procedure in theliterature (U.S. Pat. No. 4,864,051)) in diethyl ether (20 mL). Themixture was refluxed for 7 hours. Then the reaction mixture was quenchedby addition of water (2.1 mL), 15% NaOH (2.1 mL) and water (6.3 mL) at 0degrees Celsius and stirred at room temperature for 14 hours. Themixture was filtered and concentrated in vacuo to give crude material(1.5 g).

¹H-NMR (300 MHz, CDCl₃) δ 3.20 (s, 3H), 2.65 (s, 2H), 1.14 (s, 9H).

STEP 2. 1-(2-methoxy-2-methylpropyl)-1,3-dihydro-2H-benzimidazol-2-one

The title compound was prepared according to the procedure described inSteps 1, 2 and 3 of Example 1 from 2-methoxy-2-methylpropan-1-amine.

MS (ESI) m/z 221 (M+H)⁺, 219 (M−H)⁻.

STEP 3.N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(2-methyl-2-methylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described inStep 2 of Example 12 without recrystallization.

¹H-NMR (300 MHz, CDCl₃) δ 9.49 (d, J=8.1 Hz, 1H), 8.16-8.11 (m, 1H),7.31-7.23 (m, 1H), 7.22-7.10 (m, 2H), 5.97 (bs 1H), 5.65 (bs, 1H), 4.24(d, J=8.1 Hz, 1H), 3.90 (d, J=14.4 Hz, 1H), 3.85 (d, J=14.4 Hz, 1H),3.20 (s, 3H), 1.27 (s, 3H), 1.26 (s, 3H), 1.15 (s, 9H).

MS (ESI) m/z 377 (M+H)⁺.

Example 96N-[1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

STEP 1. 1-amino-2-methylpropan-2-ol hydrochloride

The title compound was prepared according to the procedure described inStep1 of Example 95 from 2-hydroxy-2-methylpropanenitrile.

¹H-NMR (300 MHz, CDCl₃, the value of free form of the title compound) δ4.39-3.96 (s, 1H), 2.61 (s, 2H), 1.17 (s, 6H).

STEP 2. 1-(2-hydroxy-2-methylpropyl)-1,3-dihydro-2H-benzimidazol-2-one

The title compound was prepared according to the procedure described inSteps 1, 2 and 3 of Example 1 from 1-amino-2-methylpropan-2-olhydrochloride.

¹H-NMR (300 MHz, CDCl₃) δ 10.43 (bs, 1H), 7.13-7.04 (m, 4H), 3.92 (s,2H), 3.63 (s, 1H), 1.33 (s 6H).

MS (ESI) m/z 207 (M+H)⁺, 205 (M−H)⁻.

STEP 3N-[(1S)-1(aminocarbonyl)-2,2-dimethylpropyl]-3-(2-hydroxy-2-methylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described inStep 2 of Example 12.

¹H-NMR (300 MHz, CDCl₃) δ 9.40 (d, J=8.1 Hz, 1H), 8.21-8.15 (m, 1H),7.22-7.15 (m, 3H), 5.84 (bs 1H), 5.54 (bs, 1H), 4.22 (d, J=8.1 Hz, 1H),2.13 (s, 2H), 2.36 (s, 1H), 1.35 (s, 6H), 1.15 (s, 9H).

MS (ESI) m/z 363 (M+H)⁺.

Anal. calcd. for C₁₈H₂₆N₄O₄ (+0.1H₂O): C, 59.36; H, 7.25; N, 15.38; O,18.01. Found: C, 59.45; H, 7.25; N, 15.00.

Example 97N-[(1S)-1-cyano-2,2-dimethylpropyl]-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydroH-benzimidazole-1-carboxamide

STEP 1. benzyl [(1S)-1-cyano-2,2-dimethylpropyl]carbamate

The title compound was prepared according to the procedure described inthe literature (Demko. Z. P.; Sharpless, K. B. Org. Lett. 2002, 4,2525-2527.) from benzyl[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]carbamate (Step1 of Example4).

MS (ESI) m/z 247 (M+H)⁺.

STEP 2.N-[(1S)-1-cyano-2,2-dimethylpropyl]-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described inStep 2 of Example 12 from (2S)-2-amino-3,3-dimethylbutanenitrile whichwas prepared from benzyl [(1S)-cyano-2,2-dimethylpropyl]carbamateaccording to the procedure described in Step 2 of Example 4.

¹H-NMR (300 MHz, CDCl₃) δ 9.45 (d, J=9.0 Hz, 1H), 8.20-8.16 (m, 1H),7.28-7.18 (m, 2H), 7.09-7.03 (m, 1H), 4.77 (d, J=9.0 Hz, 1H), 4.04-3.98(m, 2H), 3.70-3.62 (m, 4H), 2.77-2.63 (m, 2H), 2.60-2.48 (m, 4H), 1.18(s, 9H).

MS (ESI) m/z 386 (M+H)⁺.

Anal. calcd. for C₂₀H₂₇N₅O₃: C, 62.32; H, 7.06; N, 18.17; O, 12.45.Found: C, 61.99; H, 7.01; N, 17.96.

Example 98N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-5-methyl-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-carboxamide

STEP 1.5-methyl-3-(2-morpholin-4-ylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The title compound was prepared from 2-chloro-3-nitro-6 picolineaccording to the procedure described in Steps 1, 2 and 3 of Example 1.

¹H-NMR (300 MHz, CDCl₃) δ 9.94 (bs, 1H), 7.12 (d, J=7.5 Hz, 1H), 6.80(d, J=7.5 Hz, 1H), 4.18-4.05 (m, 2H), 3.70-3.55 (m, 4H), 2.83-2.71 (m,2H), 2.65-2.53 (m, 4H), 2.50 (s, 3H).

MS (ESI) m/z 263 (M+H)⁺, 261 (M−H)⁻.

STEP 2.N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-5-methyl-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-carboxamide(PF-03407918-01)

The title compound was prepared from5-methyl-3-(2-morpholin-4-ylethyl)-1,3-dihydro-2H-imidazo[4,5b]pyridin-2-oneand L-tert-leucinamide according to the procedure described in Step 4 ofExample 1.

¹H-NMR (300 MHz, DMSO-d₆) δ 11.29 (bs, 1H), 8.93 (d, J=8.7 Hz, 1H), 8.07(d, J=7.8 Hz, 1H), 7.73 (bs, 1H), 7.26 (bs, 1H), 7.06 (d, J=7.8 Hz, 1H),4.38-4.22 (m, 3H), 4.06-3.59 (m, 8H), 3.25-3.08 (m, 2H), 2.48 (s, 3H),0.99 (s, 9H).

MS (ESI) m/z 419 (M+H)⁺.

Anal. calcd. for C₂₀H₃₀N₆O₄ (0.6H₂O, 1.0 HCl, 0.1 C₄H₈O₂): C, 51.63; H,7.01; N, 17.71; O, 16.18; Cl, 7.47. Found: C, 51.88; H, 7.14; N, 17.48.

Example 99N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-5-methyl-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-carboxamide

The title compound was prepared from5-methyl-3-(2-morpholin-4-ylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-oneand L-valinamide hydrochloride according to the procedure described inStep 4 of Example 1.

¹H-NMR (300 MHz, DMSO-d₆) δ 11.22 (bs, 1H), 8.82 (d, J=8.7 Hz, 1H), 8.07(d, J=7.8 Hz, 1H), 7.73 (bs, 1H), 7.28 (bs, 1H), 7.07 (d, J=7.8 Hz, 1H),4.38-4.26 (m, 3H), 4.06-3.60 (m, 8H), 3.27-3.08 (m, 2H), 2.48 (s, 3H),2.19-2.08 (m, 1H), 0.96 (d, J=7.2 Hz, 3H), 0.89 (d, J=6.6 Hz, 3H).

MS (ESI) m/z 405 (M+H)⁺.

Anal. calcd. for C₁₉H₂₈N₆O₄ (0.5H₂O, 1.0 HCl, 0.1 C₄H₈O₂): C, 50.79; H,6.77; N, 18.32; O, 16.39; Cl, 7.73. Found: C, 50.46; H, 6.90; N, 17.93.

Example 100N-[(1S)-2,2-dimethyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)propyl]-3-[2-(4-morpholinyl)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

STEP 1. E,Z mixture ofN-{(1S)-1-[({[1-aminoethylidene]amino}oxy)carbonyl]-2,2-dimethylpropyl}-3-[2-(4-morpholinyl)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

To a solution ofN-({3-[2-(4-morpholinyl)ethyl]-oxo-2,3-dihydro-1H-benzimidazol-1-yl}carbonyl)-L-tert-leucine(prepared according to the procedure described in step 1 of example 3from methyl L-tert-leucinate hydrochloride) (0.18 g, 0.45 mmol) in DMF(1 mL) were added a solution of N-hydroxyethanimidamide (37 mg, 0.50mmol, Hamze, A.; Hernandez, J.-F.; Fulcrand, P.; Martinez, J. J. Org.Chem. 2003, 68, 7316-7321.) In DMF (1 mL), triethylamine (0.26 mL, 1.8mmol), HOBt (83 mg, 0.54 mmol) and WSC (0.10 g, 0.54 mmol) at roomtemperature. After 9 h, to this mixture were addedN-hydroxyethanimidamide (20 mg, 0.26 mmol), triethylamine (0.10 mL, 0.70mmol), HOBt (10 mg, 0.06 mmol) and WSC (20 mg, 0.10 mmol). After 13hours, the reaction was quenched by addition of sat. aq. sodiumbicarbonate (10 mL) and extracted with ethyl acetate (20 mL×2). Thecombined organic layers were washed with water (10 mL×2), brine (20 mL)and dried over sodium sulfate, filtered and concentrated. The residuewas purified by column chromatography on silica gel eluting withdichloromethane/methanol (10/1) to afford 0.12 g (57%) of the titlecompound.

MS (ESI) m/z 461 (M+H)⁺.

STEP 2.N-[(1S)-2,2-dimethyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)propyl]-3-[2-(4-morpholinyl)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

To a solution ofN-{(1S)-1-[({[aminoethylidene]amino}oxy)carbonyl]-2,2-dimethylpropyl}-3-[2-(4-morpholinyl)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide(0.11 g, 0.24 mmol) in toluene (5 mL) was added p-toluenesulfonic acidmonohydrate (4 mg, 0.02 mmol) and the mixture was refluxed for 6 hours.Then the reaction was cooled to room temperature and quenched byaddition of water (10 mL) and extracted with ethyl acetate (20 mL×2).The combined organic layers were washed with brine (20 mL) and driedover sodium sulfate, filtered and concentrated. The residue was purifiedby preparative TLC eluting with dichloromethane/methanol (10/1) toafford 62 mg (58%) of the title compound. The subsequentrecrystallization from ethyl acetate and hexane followed by filtrationgave 48 mg of the title compound as white solid.

¹H-NMR (300 MHz, CDCl₃)

9.68 (d, J=8.1 Hz, 1H), 8.15 (d, J=8.1. Hz, 1H), 7.30-7.11 (m, 2H),7.08-7.01 (m, 1H), 5.18 (d, J=8.1 Hz, 1H), 4.09-4.00 (m, 2H), 3.72-3.63(m, 4H), 2.75-2.67 (m, 2H), 2.61-2.48 (m, 4H), 2.41 (s, 3H), 1.12 (s,9H).

MS (ES I) m/z 443 (M+H)⁺.

Anal. calcd. for C₂₂H₃₀N₆O₄(+0.2H₂O): C, 59.23; H, 6.87; N, 18.84; O,15.06. Found: C, 59.14; H, 7.00; N, 18.50.

Example 101N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(3-hydroxy-3-methylbutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1carboxamide

STEP 1. 3-hydroxy-3-methylbutanenitrile

To a solution of 1-chloro-2-methylpropan-2-ol (17 g, 0.16 mol) inethanol (320 mL) and water (55 mL) was added sodium cyanide (9.4 g, 0.19mol) and the mixture was refluxed. After 3 hours, the mixture was cooledto room temperature and concentrated in vacuo. To the residue was addedwater and extracted with ethyl acetate. The combined organic layers weredried over magnesium sulfate and concentrated to give 14 g (90%) of thetitle compound.

¹H-NMR (300 MHz, CDCl₃) δ 2.54 (s, 2H), 2.03 (s, 1H), 1.42 (s, 6H).

STEP 2. 4-amino-2-methyl-2-butanol

To a solution of 3-hydroxy-3-methylbutanenitrile (16 g, 0.16 mol) in THF(350 mL) was added lithium aluminumhydride (12 g, 0.33 mol) slowly at 0degrees Celsius and the mixture was stirred for 4 hours at 50 degreesCelsius. After cooling to 0 degrees Celsius, to the mixture were addedsodium sulfate decahydrate and potassium fluoride. The mixture wasstirred for 30 minutes at room temperature and filtered through a pad ofcelite. The filtrate was concentrated in vacuo to give 14 g (84%) of thetitle compound.

¹H-NMR (300 MHz, CDCl₃)

3.03 (t, J=6.8 Hz, 2H), 1.58 (t, J=6.8 Hz, 2H), 1.24 (s, 6H).

STEP 3. 2-methyl-4-[(2-nitrophenyl)amino]-2-butanol

A solution of 1-fluoro-2-nitrobenzene (1.9 mL, 18 mmol),4-amino-2-methyl-2-butanol (1.6 g, 15 mmol) and triethylamine (6.4 mL,46 mmol) in THF (30 mL) was refluxed for 8 h. Then the reaction wasquenched by addition of water (50 mL) and extracted with ethyl acetate(50 mL×2). The combined organic layers were washed with brine (50 mL)and dried over sodium sulfate, filtered and concentrated. The residuewas purified by column chromatography on silica gel eluting withhexane/ethyl acetate (5/1-2/1) to afford 2.8 g (82%) of the titlecompound.

MS (ESI) m/z 225 (M+H)⁺.

STEP 4. 4-[(2-aminophenyl amino]-2-methyl-2-butanol

The title compound was prepared according to the procedure described instep 2 of example 1 from 2-methyl-4-[(2-nitrophenyl)amino]-2-butanol.

MS (ESI) m/z 195 (M+H)⁺.

STEP 5. 1-(3-hydroxy-3-methylbutyl)-1,3-dihydro-2H-benzimidazol-2-one

The title compound was prepared according to the procedure described instep 3 of acetate (0.10 L) and washed with water (50 mL×2), brine (50mL), dried over sodium sulfate, filtered and concentrated to give acrude material. The another batch starting from 1.3 g of2-chloro-3-nitrotoluene was combined to this crude material and thecombined crude products were purified by column chromatography on silicagel eluting with hexane/ethyl acetate (3/1) to afford 2.6 g (77%) of thetitle compound.

MS (ESI) m/z 227 (M+H)⁺.

STEP 2.7-methyl-1-[2-(methylthio)ethyl]-1,3-dihydro-2H-benzimidazol-2-one

To a solution of 2-methyl-N-[2-(methylthio)ethyl]-6-nitroaniline (2.6 g,12 mmol) in ethanol (6.0 mL) was added a solution of Tin(II) chloridedihydrate (7.9 g, 35 mmol) in concd. hydrochloric acid (8.0 mL) at 0degrees Celsius and warmed to room temperature. After 4 hours, thereaction was quenched by addition of 6N sodium hydroxide (100 mL) andextracted with ethyl acetate (100 mL×2), dried over sodium sulfate,filtered and concentrated. The crude material was dissolved in THF (50mL) and to this solution was added CDI (2.3 g, 14 mmol) and the mixturewas stirred at room temperature. After 12 hours, to the mixture wasadded CDI (1.5 g, 6.7 mmol) and the reaction mixture was refluxed for 5hours. Then the mixture was cooled to room temperature and evaporated todryness. To this was added water (100 mL) and extracted with ethylacetate (100 mL×2). The combined organic layers were washed with water(50 mL), brine (50 mL), dried over sodium sulfate, filtered andconcentrated. The obtained material was dissolved in methanol (30 mL)and to this solution was added 2N sodium hydroxide (3 mL) and stirred atroom temperature for 2 hours. Then the mixture was quenched by additionof sat. aq. sodium bicarbonate (50 mL) and extracted with ethyl acetate(100 mL×2). The combined organic layers were washed with water (50 mL),brine (50 mL), dried over sodium sulfate, filtered and concentrated. Theresidue was purified by column chromatography on silica gel eluting withdichloromethane/methanol (20/1-10/1) to afford 1.8 g (69%) of the titlecompound.

MS (ESI) m/z 223 (M+H)⁺.

STEP 3.N-{(1S)-1-[(dimethylamino)carbonyl]-2,2-dimethylpropyl}-4-methyl-3-[2-methylthio)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

To a solution of7-methyl-1-[2-(methylthio)ethyl]-1,3-dihydro-2H-benzimidazol-2-one (0.21g, 0.93 mmol) in 1,2-dichloroethane (5 mL) were added triethylamine(0.43 mL, 3.1 mmol) and 4-nitrophenyl chloroformate (0.23 g, 1.1 mmol)at 0 degrees Celsius and the mixture was stirred at room temperature for4 hours. Then to this mixture was added a solution ofN,N-dimethyl-tert-leucinamide (ca. 1.4 mmol, prepared according to theprocedure described in steps 1 and 2 of example 3 from dimethylaminehydrochloride) in 1,2-dichloroethane (3 mL) at 0 degrees Celsius andstirred at room temperature. After 14 hours, the reaction was quenchedby addition of water (50 mL) and extracted with dichloromethane (50mL×2). The combined organic layers were washed with water (30 mL×4),brine (30 mL), dried over sodium sulfate, filtered and concentrated invacuo. The residue was purified by preparative TLC eluting withdichloromethane/methanol (10/1) to afford 0.31 g (83%) of the titlecompound.

¹H-NMR (300 MHz, CDCl₃)

9.56 (d, J=9.0 Hz, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.07-6.98 (m, 1H), 6.94(d, J=7.5 Hz, 1H), 4.92 (d, J=9.0 Hz, 1H), 4.32-4.22 (m, 2H), 3.23 (s,3H), 3.00 (s, 3H), 2.85-2.77 (m, 2H), 2.59 (s, 3H), 2.22 (s, 3H), 1.10(s, 9H).

MS (ESI) m/z 407 (M+H)⁺.

Anal. calcd. for C₂₀H₃₀N₄O₃S: C, 59.09; H, 7.44; N, 13.78; O, 11.81; S,7.89. Found: C, 58.97; H, 7.45; N, 13.67.

Example 103N-{(1S)-1-[(dimethylamino)carbonyl]-2,2-dimethylpropyl}-4-methyl-3-[2-(methylsulfonyl)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

To a solution ofN-{(1S)-1-[(dimethylamino)carbonyl]-2,2-dimethylpropyl}-4-methyl-3-[2-methylthio)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide(EXAMPLE 102, 0.27 g, 0.67 mmol) in dichloromethane (22 mL) were addedm-CPBA (0.57 g, 2.3 mmol) and sodium bicarbonate (0.15 g, 1.7 mmol) atroom temperature and stirred for 14 hours. Then the reaction wasquenched by addition of sat. aq. sodium thiosulfate (50 mL) and theaqueous layer was extracted with dichloromethane (50 mL). The combinedorganic layers were washed with water (30 mL), brine (30 mL), dried oversodium sulfate, filtered and concentrated. The residue was purified bypreparative TLC eluting with dichloromethane/methanol (10/1) to afford0.19 g (66%) of the title compound. The obtained solid was thenrecrystallized from hexane/ethylacetate to give 164 mg of the titlecompound.

¹H-NMR (300 MHz, CDCl₃)

9.45 (d, J=8.7 Hz, 1H), 8.11 (d, J=7.5 Hz, 1H), 7.10-7.05 (m, 1H), 6.98(d, J=7.2 Hz, 1H), 4.92 (d, J=8.7 Hz, 1H), 4.66-4.55 (m, 2H), 3.53-3.44(m, 2H), 3.22 (s; 3H), 3.04 (s, 3H), 2.99 (s, 3H), 2.64 (s, 3H), 1.10(s, 9H).

MS (ESI) m/z 439 (M+H)⁺.

Anal. calcd. for C₂₀H₃₀N₄O₅S: C, 54.78; H, 6.90; N, 12.78; O, 18.24; S,7.31. Found: C, 54.42; H, 6.90; N, 12.50.

mp 190.7 degrees Celsius.

Example 104N-[(1S)-(hydroxymethyl)-2,2-dimethylpropyl]-3-[2-(methylsulfonyl)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

STEP 1. N-[2-(methylthio)ethyl]-2-nitroaniline

The title compound was prepared according to the procedure described instep 1 of example 1 from 2-(methylthio)ethylamine.

MS (ESI) m/z 213 (M+H)⁺.

STEP 2. 1-[2-(methylthio)ethyl]-1,3-dihydro-2H-benzimidazol-2-one

The title compound was prepared according to the procedure described instep 2 of EXAMPLE 102.

MS (ESI) m/z 209 (M+H)⁺.

STEP 3.N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]-3-[2-(methylsulfonyl)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described insteps 3 of EXAMPLE 102 and EXAMPLE 103 starting from L-tert-leucinol.

¹H-NMR (270 MHz, CDCl₃)

8.89 (d, J=8.4 Hz, 1H), 8.24-8.21 (m, 1H), 7.30-7.14 (m, 3H), 4.41 (t,J=7.3 Hz, 2H), 4.04-3.86 (m, 2H), 3.73-3.61 (m, 1H), 3.49 (t, J=7.3 Hz,2H), 2.96 (s, 3H), 2.27-2.18 (m, 1H), 1.05 (s, 9H).

MS (ESI) m/z 384 (M+H)⁺.

Anal. calcd. for C₁₇H₂₅N₃OFS (+0.2H₂O): C, 52.75; H, 6.61; N, 10.86; O,21.49; S, 8.28. Found: C, 52.44; H, 6.61; N, 10.68.

Example 105N-[(1S)-2,2-dimethyl-1-(2-methyl-2H-tetrazol-5-yl)propyl]-3-(3-hydroxy-3-methylbutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

STEP 1. benzyl[(1S)-2,2-dimethyl-1-(2H-tetrazol-5-yl)propyl]carbamate

The title compound was prepared according to the procedure described theliterature (Olah, G. A. et al. Synthesis 1980, 657-658.; Demko, Z. P.and Sharpless, K. B. Org. Lett. 2002, 4, 2525-2527.) starting frombenzyl[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]carbamate.

MS (ESI) m/z 290 (M+H)⁺.

STEP 2.benzyl[(1S)-2,2-dimethyl-1-(2-methyl-2H-tetrazol-5-yl)propyl]carbamate

A suspension ofbenzyl[(1S)-2,2-dimethyl-1-(2H-tetrazol-5-yl)propyl]carbamate (0.41 g,1.4 mmol), potassium carbonate (1.0 g, 7.0 mmol) and methyl iodide (0.35mL, 5.6 mmol) in acetone (7 mL) was stirred at 0 degrees Celsius for 10minutes and warmed to room temperature. After 5 hours, the reactionmixture was filtered and concentrated. The residue was purified bycolumn chromatography on silica gel eluting with hexane/ethyl acetate(8/1-4/1-1/1) to afford 0.29 g (68%) of the title compound.

MS (ESI) m/z 304 (M+H)⁺.

STEP 3. (1S)-2,2-dimethyl-1-(2-methyl-2H-tetrazol-5-yl)-1-propanamine

The title compound was prepared according to the procedure described instep 2 of example 3 starting frombenzyl[(1S-2,2-dimethyl-1-(2-methyl-2H-tetrazol-5-yl)propyl]carbamate.

MS (ESI) m/z 170 (M+H)⁺.

STEP 4.N-[(1S)-2,2-dimethyl-1-(2-methyl-2H-tetrazol-5-yl)propyl]-3-(3-hydroxy-3-methylbutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

The title compound was prepared according to the procedure described instep 4 of EXAMPLE 101 starting from1-(3-hydroxy-3-methylbutyl)-1,3-dihydro-2H-benzimidazol-2-one and(1S)-2,2-dimethyl-1-(2-methyl-2H-tetrazol-5-yl)-1-propanamine.

¹H-NMR (300 MHz, CDCl₃)

9.67 (d, J=9.3 Hz, 1H), 8.16 (dd, J=7.2, 1.5 Hz, 1H), 7.23-7.12 (m, 2H),7.06 (d, J=7.2 Hz, 1H), 5.30 (d, J=9.3 Hz, 1H), 4.34 (s, 3H), 4.11-4.06(m, 2H), 1.95-1.90 (m, 2H), 1.34 (s, 6H), 1.08 (s, 9H).

MS (ESI) m/z 416 (M+H)⁺.

Anal. calcd. for C₂₀H₂₉N₇O₃ (+0.1H₂O): C, 57.57; H, 7.05; N, 23.50; O,11.89. Found: C, 57.29; H, 7.13; N, 23.10.

Example 106N-[(1S)-2,2-dimethyl-1-(5-methyl-1,3,4-thiadiazol-2-yl)propyl]-3-(3-hydroxy-3-methylbutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-a-carboxamide

STEP 1.benzyl{(1S)-2,2-dimethyl-1-(5-methyl-1,3,4-thiadiazol-2-yl)propyl}carbamate

The title compound was prepared according to the procedure described inthe literature (Alker, D. et al. J. Med. Chem. 1989, 32, 2381-2388.)starting from N-[(benzyloxy)carbonyl]-tert-leucine.

¹H-NMR (300 MHz, CDCl₃) δ 7.41-7.28 (m, 5H), 5.79-5.75 (m, 1H),5.14-4.99 (m, 3H), 2.78 (s, 3H), 1.30 (s, 9H).

MS (ESI) m/z 320 (M+H)⁺.

STEP 2.(1S)-2,2-dimethyl-1-(5-methyl-1,3,4-thiadiazol-2-yl)-1-propSnaminehydrochloride

A solution ofbenzyl{(1S)-2,2-dimethyl-1-(5-methyl-1,3,4-thiadiazol-2-yl)propyl}carbamate(ca. 0.6 mmol) in anhydrous hydrogen bromide in acetic acid (25%solution, 1 mL) was stirred at room temperature for 4 hours. Then tothis mixture was added ether (50 mL) (precipitate was observed.). Thesupernatant fluid was decanted. The process of wash with ether followedby decantation was repeated twice and the resultant solid was dried invacuo to give the crude material of the title compound.

¹H-NMR (300 MHz, DMSO-d₆) δ 4.91-4.89 (m, 1H), 2.77 (s, 3H), 1.01 (s,9H).

STEP 3.N-[(1S)-2,2-dimethyl-1-(5-methyl-1,3,4-thiadiazol-2-yl)propyl]-3-(3-hydroxy-3-methylbutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-a-carboxamide

To a solution of1-(3-hydroxy-3-methylbutyl)-1,3-dihydro-2H-benzimidazol-2-one (0.12 g,0.55 mmol) in 1,2-dichloroethane (18 mL) were added triethylamine (0.25mL, 1.8 mmol) and 4-nitrophenyl chloroformate (0.13 g, 0.66 mmol) at 0degrees Celsius and the mixture was stirred at room, temperature for 4hours. Then to this mixture was added a suspension of(1S)-2,2-dimethyl-1-(5-methyl-1,3,4-thiadiazol-2-yl)-propanaminehydrochloride and triethylamine (0.2 mL, 1.4 mmol) in 1,2-dichloroethane(5 mL) at 0 degrees Celsius and stirred room temperature. After 14hours, the reaction was quenched by addition of water (30 mL) andextracted with dichloromethane (30 mL×3). The combined organic layerswere washed with water (30 mL×5), brine (30 mL), dried over sodiumsulfate, filtered and concentrated in vacuo. The residue was purified bypreparative TLC twice eluting with THF/hexane (1/1) anddichloromethane/methanol (10/1) respectively to afford 15 mg (6%) of thetitle compound.

¹H-NMR (300 MHz, CDCl₃)

9.70 (d, J=10.2 Hz, 1H), 8.15 (d, J=9.0 Hz, 1H), 7.22-7.13 (m, 2H), 7.07(d, J=8.7 Hz, 1H), 5.31 (d, J=9.0 Hz, 1H), 4.13-4.05 (m, 2H), 2.74 (s,3H), 1.98-1.88 (m, 2H), 1.34 (s, 6H), 1.15 (s, 9H).

MS (ESI) m/z 432 (M+H)⁺.

Example 107N-[(1S)-(1-aminocarbonyl)-2,2-dimethylpropyl]-3-(3-amino-3-methylbutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamidehydrochloride

STEP 1. N-{1,1-dimethyl-3-[(2-nitrophenyl)amino]propyl}formamide

To a mixture of 2-methyl-4-[(2-nitrophenyl)amino]butan-2-ol (1.7 g, 7.8mmol) and trimethylsilyl cyanide (4.2 mL, 31 mmol) was added conod.sulfuric acid at −30 degrees Celsius and the mixture was warmed up toroom temperature. After stirring for 24 hours, the reaction mixture wascooled to 0 degrees Celsius and to the mixture was added water andstirred for 30 minutes at room temperature. The mixture was poured intoaq. potassium carbonate and extracted with dichloromethane. The combinedorganic layers were dried over magnesium sulfate and concentrated invacuo. The crude product was purified by column chromatography on silicagel eluting with dichloromethane/methanol (25/1) to give 1.3 g (66%) ofthe title compound.

¹H-NMR (300 MHz, CDCl₃) (a mixture of rotamers) δ 8.34-7.84 (m, 3H),7.53-7.36 (m, 1H), 6.96-6.57 (m, 2H), 6.02 (bs, 0.2H), 5.35 (bs, 0.8H),3.53-3.31 (m, 2H), 2.38-1.97 (m, 2H), 1.44 (s, 6H).

MS (ESI) m/z 252 (M+H)⁺.

STEP 2.N-[1,1-dimethyl-3-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)propyl]formamide

A mixture of N-{1,1-dimethyl-3-[(2-nitrophenyl)amino]propyl}formamide(1.3 g, 5.1 mmol) and palladium on charcoal (0.13 g) in THF (20 mL) wasstirred under hydrogen atmosphere (4 atm) for 6 hours. The mixture wasfiltered through a celite pad and the filtrate was concentrated invacuo.

The obtained crude product was dissolved in THF (20 mL) and to thissolution was added CDI (1.0 g, 6.2 mmol). After stirring for 16 hours atroom temperature, water was added to the solution. Then it was extractedwith ethyl acetate. The combined organic layers were dried overmagnesium sulfate and concentrated. The residue was purified by columnchromatography on silica gel eluting with dichloromethane/methanol(25/1) to give 1.1 g of a mixture of the title compound and an impurity.

MS (ESI) m/z 248 (M+H)⁺.

STEP 3. 1-(3-amino-3-methylbutyl)-1,3-dihydro-2H-benzimidazol-2-one

A mixture ofN-[1,1-dimethyl-3-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)propyl]formamide(1.1 g) and hydrogen chloride-methanol (80-90% methanol, 18 mL) wasstirred at rt for 50 h. The mixture was concentrated in vacuo and theresidue was basified by aq. potassium carbonate and the mixture wasextracted with dichloromethane. The combined organic layers were driedover sodium sulfate and concentrated to give 0.81 g (3.7 mmol, 73% for 3steps) of the title compound.

¹H-NMR (300 MHz, CDCl₃) δ 7.14-6.97 (m, 4H), 4.02 (t, J=7.5 Hz, 2H),1.83 (t, J=7.5 Hz, 2H), 1.22 (s, 6H).

MS (ESI) m/z 220 (M+H)⁺.

STEP 4. tert-butyl[1,1-dimethyl-3-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)propyl]carbamate

-   To a suspension of    1-(3-amino-3-methylbutyl)-1,3-dihydro-2H-benzimidazol-2-one (0.22 g,    1.0 mmol) in dichloromethane (2 mL) and THF (2 mL) were added    triethylamine (0.28 mL, 2.0 mmol) and di-tert-butyl dicarbonate    (0.24 g, 1.1 mmol) at room temperature. After stirring for 1.5    hours, the mixture was diluted with ethyl acetate and washed with    water and brine, dried over magnesium sulfate and concentrated in    vacuo. The residue was purified by column chromatography on silica    gel eluting with dichloromethane/methanol (25/1) to give 0.32 g    (quantitative yield) of the title compound.

¹H-NMR (300 MHz, CDCl₃) δ 9.51 (bs, 1H), 7.19-6.95 (m, 4H), 3.93 (t,J=8.3 Hz, 2H), 3.49 (bs, 1H), 2.18 (t, J=8.3 Hz, 2H), 1.44 (s, 9H), 1.36(s, 6H).

MS (ESI) m/z 320 (M+H)⁺.

STEP 5. tert-butyl{3-[3-({[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]amino}carbonyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]-1,1-dimethylpropyl}carbamate

The title compound was prepared according to the procedure described inStep 4 of Example 1 from tert-butyl[1,1-dimethyl-3-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)propyl]carbamate.

¹H-NMR (300 MHz, CDCl₃) δ 9.46 (d, J=9.0 Hz, 1H), 8.15 (d, J=6.0 Hz,1H), 7.37-7.04 (m, 3H), 5.80 (bs, 1H), 5.42 (bs, 1H), 4.54 (s, 1H), 4.22(d, J=9.0 Hz, 1H), 4.00-3.83 (m, 2H), 2.31-2.08 (m, 2H), 1.42 (s, 6H),1.36 (s, 9H), 1.16 (s, 9H).

MS (ESI) m/z 476 (M+H)⁺.

STEP 6.N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(3-amino-3-methylbutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamidehydrochloride

To a solution of tert-butyl{3-[3-({[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]amino}carbonyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]-1,1-dimethylpropyl}carbamate(0.23 g, 0.48 mmol) in methanol (1.5 mL) was added hydrogenchloride-methanol (80-90% methanol, 6 mL). After stirring at roomtemperature for 40 hours, the reaction mixture was concentrated invacuo. The residue was added a mixture of hexane and ethyl acetate andthe precipitate was filtered and dried to give 0.18 g (88%) of the titlecompound.

¹H-NMR (DMSO-d₆) δ 9.19 (d, J=9.0 Hz, 1H), 8.16 (bs, 2H), 8.06 (d, J=6.0Hz, 1H), 7.67 (bs, 1H), 7.41-7.10 (m, 4H), 4.27 (d, J=9.0 Hz, 1H), 4.02(t, J=7.5 Hz, 2H), 1.98 (t, J=7.5 Hz, 2H), 1.36 (s, 6H), 1.00 (s, 9H).

MS (ESI) m/z 376 (M+H)⁺.

Anal. calcd. for C₁₉H₂₉N₅O₃ (+3.0H₂O, 1.3 HCl): C, 47.85; H, 7.67; N,14.68; O, 20.13; Cl, 9.66.

Found: C, 47.74; H, 7.43; N, 14.71.

Following Examples 108 to 149 were prepared according to the proceduredescribed in step 4 of Example 1.

Example 108Rel-3-[2-(dimethylamino)ethyl]-N-[(1R,2S)-2-hydroxycyclohexyl]-4-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, DMSO) δ 10.63 (bs, 1H), 8.76 (d, J = 7.2 Hz, 1H), 8.01(d, J = 7.5 Hz, 1H), 7.09-7.00 (m, 1H), 4.88 (bs, 1H), 4.45 (t, J = 6.6Hz, 2H), 3.55-3.45 (m, 1H), 3.42 (t, J = 6.6 Hz, 2H), 2.87 (s, 6H), 2.59(s, 3H), 2.10-1.98 (m, 1H), 1.93-1.80 (m, 1H), 1.69-1.51 (m, 2H),1.36-1.15 (m, 4H). MS (ESI) m/z 361 (M + H)⁺. Anal. calcd. forC₁₉H₂₈N₄O₃ (+1 HCl· 0.2 H₂O): C, 56.98; H, 7.40; N, 13.99; O, 12.78; Cl,8.85. Found: C, 56.58; H, 7.41; N, 13.81. Example 109N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-{2-[methyl(methylsulfonyl)amino]ethyl}-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (270 MHz, CDCl₃) δ 9.38 (d, J = 7.8 Hz, 1H), 8.17 (d, J = 7.3 Hz,1H), 7.31 -7.16 (m, 3H), 5.82 (bs, 1H), 5.48 (bs, 1H), 4.22 (d, J = 7.8Hz, 1H), 4.19-4.09 (m, 2H), 3.53-3.45 (m, 2H), 2.93 (s, 3H), 2.80 (s,3H), 1.15 (s, 9H).MS (ESI) m/z 426 (M + H)⁺. Example 110N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclopropylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-carboxamide

¹H-NMR (300 MHz, DMSO-d₆) δ 9.01 (d, J = 9.0 Hz, 1H), 8.21-8.15 (m, 2H),7.69 (bs, 1H), 7.24-7.17 (m, 2H), 4.26 (d, J = 9.0 Hz, 1H), 3.86-3.65(m, 2H), 1.34-1.17 (m, 1H), 0.99 (s, 9H), 0.54-0.35 (m, 4H). MS (ESI)m/z 346 (M +H)⁺. Anal. calcd. for C₁₇H₂₃N₅O₃: C, 59.12; H, 6.71; N,20.28; O, 13.90. Found: C, 58.73; H, 6.77; N; 19.93. Example 111N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclopropyl-methyl)-4-methyl-2-oxo-2,3-dihydro-1H-Imidazo[4,5-c]pyridine-1-carboxamide.

¹H-NMR (300 MHz, CDCl₃) δ 9.46 (d, J = 8.1 Hz, 1H), 8.30 (d, J = 5.7 Hz,1H), 8.02 (d, J = 5.7 Hz, 1H), 5.75 (bs, 1H), 5.52 (bs, 1H), 4.19 (d, J= 8.1 Hz, 1H), 4.08-3.95 (m, 2H), 2.87 (s, 3H), 1.25-1.02 (m, 10H),0.65-0.46 (m, 4H). MS (ESI) m/z 360 (M + H)⁺. Anal. calcd. forC₁₈H₂₅N₅O₃ (+0.7 H₂O): C, 58.11; H, 7.15; N, 18.82; O, 15.91. Found: C,58.24; H, 7.12; N, 18.45. Example 112N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-(1,1,3,3-tetramethylbutyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (270 MHz, CDCl₃) δ 9.72 (d, J =7.8 Hz, 1H), 8.29-8.25 (m, 1H),7.48-7.44 (m, 1H), 7.16-7.09 (m, 2H), 5.88 (bs, 1H), 5.50 (bs, 1H), 4.22(d, J = 7.8 Hz, 1H), 2.17 (d, J = 15.4 Hz, 1H), 2.03 (d, J = 15.4 Hz,1H), 1.90 (s, 3H), 1.89 (s, 3H), 1.15 (s, 9H), 0.88 (s, 9H). MS (El) m/z402 (M)⁺. Anal. calcd. for C₂₂H₃₄N₄O₃ (+0.5 H₂O): C, 64.21; H, 8.57; N,13.61; O, 13.61. Found: C, 64.54; H, 8.70; N, 13.44. Example 113N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-6-methyl-3-[2-(4-morpholinyl)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (270 MHz, DMSO-d₆) δ 10.74 (bs, 1H), 9.08 (d, J = 9.2 Hz, 1H),7.86 (bs, 1H), 7.64 (bs, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.16 (bs, 1H),7.04 (d, J = 7.8 Hz, 1H), 4.35-4.25 (m, 2H), 4.19 (d, J = 9.2 Hz, 1H),4.02-3.84 (m, 2H), 3.80-3.35 (m, OH), 3.20-3.00 (m, 2H), 2.32 (s, 3H),0.94 (s, 9H). MS (ESI) m/z 418 (M + H)⁺. Anal. calcd. for C₂₁H₃₁N₅O₄(+1.0 HCl, 0.2 C₄H₈O₂, 1.2 H₂O): C, 53.09; H, 7.36; N, 14.20; O, 18.17;Cl, 7.19. Found: C, 53.04; H, 7.27; N, 14.26. Example 114N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[2-(dimethyl-amino)ethyl]-2-oxo-4-(trifluoromethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, CDCl₃) δ 9.20 (d, J = 8.7 Hz, 1H), 8.47 (d, J = 8.1 Hz,1H), 7.68 (bs, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.37-7.29 (m, 1H), 7.24(bs, 1H), 4.26 (d, J = 8.7 Hz, 1H), 4.11-3.98 (m, 2H), 3.41-3.25 (m,2H), 2.20 (s, 6H), 0.98 (s, 9H). MS (ESI) m/z 430 (M + H)⁺. Example 115N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-5-fluoro-3-[2-(4-morpholinyl)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, DMSO-d₆) δ 11.03 (bs, 1H), 9.00 (d, J = 9.6 Hz, 1H),8.02 (dd, J = 9.6, 5.4 Hz, 1H), 7.69 (bs, 1H), 7.54 (d, J = 7.5 Hz, 1H),7.22 (bs, 1H), 7.03 (dt, J = 9.6, 3.0 Hz, 1H), 4.42-4.30 (m, 2H), 4,26(d, J = 9.6 Hz, 1H), 4.09-3.93 (m, 2H), 3.85-3.42 (m, 6H), 3.26-3.08 (m,2H), 0.99 (s, 9H). MS (ESI) m/z 422 (M + H)⁺. Anal. calcd. forC₂₀H₂₈N₅O₄F (+1.0 HCl, 0.1 C₈H₁₄, 0.5 H₂O): C, 52.03; H, 6.66; N, 14.73;O, 15.14; F, 4.00; Cl, 7.46. Found: C, 51.67; H, 6.81; N, 14.40. Example116 N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(3-hydroxy-3-methylbutyl)-4-methyl-2-oxo-2,3-dihydro-1H-benzimldazole-1-carboxamide

¹H-NMR (300 MHz, DMSO-d₆) δ 9.34 (d, J = 9.0 Hz, 1H), 7.98 (dd, J = 7.2,2.1 Hz, 1H), 7.66 (bs, 1H), 7.20 (bs, 1H), 7.06-6.99 (m, 2H), 4.51 (s,1H), 24.24 (d, J = 9.0 Hz, 1H), 4.20-4.09 (m, 2H), 2.61 (s, 3H),1.79-1.70 (m, 2H), 1.20 (s, 6H), 0.99 (s, 9H). MS (ESI) m/z 391 (M +H)⁺. Anal. calcd. for C₂₀H₃₀N₄O₄: C, 61.52; H, 7.74; N) 14.35; O, 16.39.Found: C, 61.17; H, 7.71; N, 14.20. Example 117N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(1-hydroxy-cyclobutyl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1- carboxamide

¹H-NMR (300 MHz, DMSO-d₆) δ 9.24 (d, J = 8.7 Hz, 1H), 8.03 (d, J = 6.6Hz, 1H), 7.68 (bs, 1H), 7.40 (bs, J = 8.1 Hz, 1H), 7.22-7.10 (m, 3H),5.40 (s, 1H), 4.27 (d, J = 8.7 Hz, 1H), 4.01 (d, J = 15.0 Hz, 1H), 3.94(d, J = 15.0 Hz, 1H), 2.20-2.14 (m, 2H), 2.00-1.90 (m, 2H), 1.71-1.58(m, 2H), 0.99 (s, 9H). MS (ESI) m/z 375 (M + H)⁺. Anal. calcd. forC₁₉H₂₆N₄O₄ (+0.1 H₂O): C, 60.65; H, 7.02; N, 14.89; O, 17.44. Found: C,60.44; H, 7.03; N, 14.62. mp 158 degrees Celsius. Example 118N-((1S)-2,2-dimethyl-1-{[(methylsulfonyl)amino]methyl}propyl)-3-[2-(4-morpholinyl)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazolone-1-carboxamide

¹H-NMR (300 MHz, CDCl₃) δ 9.07 (d, J = 8.7 Hz, 1H), 8.20-8.17 (m, 1H),7.24-7.17 (m, 2H), 7.07-7.04 (m, 1H), 5.02-4.93 (m, 1H), 4.07-3.89 (m,3H), 3.68-3.56 (m, 5H), 3.15 (ddd, J = 12.3, 10.2, 4.2 Hz, 1H), 2.97 (s,3H), 2.77-2.65(m, 2H), 2.63-2.47 (m, 4H), 1.06 (s, 9H). MS (ESI) m/z 468(M + H)⁺. Anal. calcd. for C₂₁H₃₃N₅O₅S: C, 53.33; H, 7.16; N, 14.81; O,17.93; S, 6.78. Found: C, 53.12; H, 7.02; N, 14.68. Example 119N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[2-(dimethyl-amino)ethyl]-4-fluoro-2-oxo-2,3-dihydro-1H-benzimidazole- 1-carboxamide

¹H-NMR (300 MHz, DMSO-d₆) δ 9.97 (bs, 1H), 9.08 (d, J = 8.7 Hz, 1H),7.97-7.90 (m, 1H), 7.70 (bs, 1H), 7.28-7.14 (m, 3H), 4.38-4.27 (m, 3H),3.54-3.42 (m, 2H), 2.89 (s, 6H), 0.99 (s, 9H). MS (ESI) m/z 380 (M +H)⁺. Anal. calcd. for C₁₈H₂₆N₅O₃F (+1.0 HCl, 0.5 IPA, 0.5 H₂O): C,51.48; H, 7.09; N, 15.39; O, 14.07; F, 4.18; Cl, 7.79. Found: C, 51.71;H, 7.20; N, 15.19. Example 1203-(3-hydroxy-3-methylbutyl)-N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, CDCl₃) δ 9.05 (d, J = 8.7 Hz, 1H), 8.21 (dd, J = 7.2,1.5 Hz, 1H), 7.24-7.14 (m, 2H), 7.06 (dd, J = 7.2, 1.5 Hz, 1H),4.09-3.88 (m, 4H), 3.70-3.63 (m, 1H), 2.41 (bs, 1H), 1.94-1.89 (m, 2H),1.77 (bs, 1H), 1.34 (s, 6H), 1.05 (s, 9H). MS (ESI) m/z 364 (M + H)⁺.Anal. calcd. for C₁₉H₂₉N₃O₄ (+0.3 H₂O): C, 61.87; H, 8.09; N, 11.39; O,18.65. Found: C, 61.93; H, 8.18; N, 11.37. Example 121N-[(1S)-2,2-dimethyl-1-(1-methyl-1H-tetrazol-5-yl)propyl]-3-(3-hydroxy-3-methylbutyl)-2-oxo-2,3-dihydro-1 H-benzimidazole-1-carboxamide

¹H-NMR (270 MHz, CDCl₃) δ 9.74-9.70 (m, 1H), 8.06 (d, J = 8.1 Hz, 1H),7.23-7.05 (m, 3H), 5.09 (d, J = 7.8 Hz, 1H), 4.22 (s, 3H), 4.09-4.03 (m,2H), 1.94-1.88 (m, 2H), 1.34 (s, 3H), 1.33 (s, 3H), 1.17 (s, 9H). MS(ESI) m/z 416 (M + H)⁺. Example 122N-{(1S)-2,2-dimethyl-1-[(methylsulfonyl)methyl]propyl}-3-(3-hydroxy-3-methylbutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, CDCl₃) δ 9.14 (d, J = 9.6 Hz, 1H), 8.22 (d, J = 6.6 Hz,1H), 7.24-7.16 (m, 2H), 7.09-7.07 (m, 1H), 4.54-4.40 (m, 1H), 4.15-3.97(m, 2H), 3.34 (d, J = 14.7 Hz, 1H), 3.11 (dd, J = 14.7, 10.2 Hz, 1H),3.02 (s, 3H), 1.94-1.89 (m, 2H), 1.33 (s, 6H), 1.05 (s, 9H). MS (ESI)m/z 426 (M + H)⁺. Anal. calcd. for C₂₀H₃₁N₃O₅S (+0.3 H₂O): C, 55.74; H,7.39; N, 9.75; O, 19.68; S, 7.44. Found: C, 55.56; H, 7.42; N, 9.66.Example 123 3-(3-hydroxy-3-methylbutyl)-N-[1-(hydroxymethyl)cyclopentyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, CDCl₃) δ 9.06 (s, 1H), 8.18 (d, J = 7.2 Hz, 1H),7.25-7.14 (m, 2H), 7.09-7.02 (m, 1H), 4.09-3.93 (m, 3H), 3.84-3.76 (m,2H), 1.94-1.66 (m, 10H), 1.33 (s, 6H). MS (ESI) m/z 362 (M + H)⁺. Anal.calcd. for C₁₉H₂₇N₃O₄: C, 62.51; H, 7.57; N, 11.51; O, 18.41. Found: C,62.41; H, 7.60; N, 11.24. Example 124N-[1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[(1-hydroxycyclohexyl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (270 MHz, CDCl₃) δ 9.42 (d, J = 7.9 Hz, 1H), 8.19-8.16 (m, 1H),7.22-7.07 (m, 3H), 5.90 (br, 1H), 5.58 (br, 1H), 4.22 (d, J = 7.9 Hz,1H), 3.89 (s, 2H), 2.28 (d, J = 3.3 Hz, 1H), 1.14 (s, 9H), 1.64-1.52 (m,10H) MS (ESI) m/z 403 (M + H)⁺. Example 125N-[1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-(tetrahydrofuran-2-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (270 MHz, CDCl₃) δ 9.47-9.44 (m, 1H), 8.17 (d, J = 7.3 Hz, 1H),7.24-7.13 (m, 3H), 4.30-4.19 (m, 2H), 4.08-3.70 (m, 4H), 2.11-1.68 (m,4H), 1.15 (s, 9H). MS (ESI) m/z 375 (M + H)⁺. Example 126N-[2,2-dimthyel-1-(pyrrolidin-1-ylmethyl)propyl]-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (270 MHz, CDCl₃) δ 8.87 (d, J = 9.9 Hz, 1H), 8.24-8.21 (m, 1H),7.23-7.13 (m, 2H), 7.05-7.01 (m, 1H), 4.14-3.98 (m, 3H), 3.67 (t, J =4.6 Hz, 4H), 3.00-2.66 (m, 8H), 2.60-2.47 (m, 4H), 1.76-1.89 (m, 4H),1.02 (s, 9H). MS (ESI) m/z 444 (M + H)⁺. Example 127N-(1-acetyl-2,2-dimethylpropyl)-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, CDCl₃) δ 9.37 (d, J = 7.3 Hz, 1H), 8.09 (dd, J = 2.0,7.3 Hz, 1H), 7.18-7.07 (m, 2H), 6.99-6.96 (m, 1H), 4.37 (d, J = 7.3 Hz,1H), 3.95 (t, J = 6.6 Hz, 2H), 3.62-3.59 (m, 4H), 2.63 (t, J = 6.6 Hz,2H), 2.54-2.41 (m, 4H), 2.55 (s, 3H), 1.04 (s, 9H). MS (ESI) m/z 403(M + H)⁺. Example 128N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-4-methyl-2-oxo-3-(2-pyr-roliden-1-ylethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamidehydrochloride

¹H-NMR (270 MHz, CDCl₃) δ 13.1-12.8 (m, 1H), 9.41-9.23 (m, 1H),8.13-7.94 (m, 1H), 7.11-6.77 (m, 2H), 6.31-6.05 (m, 1H), 5.68-5.45 (m,1H), 4.90-4.40 (m, 2H), 4.27-3.70 (m, 3H), 3.17-2.80 (m, 1H), 2.70 (bs,3H), 2.47-1.88 (m, 4H), 1.22-0.81 (m, 13H). MS (ESI) m/z 402 (M + H)⁺.Anal. calcd. for C₂₁H₃₁N₅O₃ (+1.0 H₂O, 1.0 HCl): C, 55.32; H, 7.52; N,15.36; O, 14.04; Cl, 7.78. Found: C, 55.53; H, 7.55; N; 15.08. Example129 N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(2-hydroxy-2-methylpropyl)4-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, CDCl₃) δ 9.49 (d, J = 9.0 Hz, 1H), 8.15 (d, J = 8.3 Hz,1H), 7.07 (dd, J = 8.3, 8.3 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 5.88 (bs,1H), 5.57 (bs, 1H), 4.23 (s, 2H), 4.21 (d, J = 9.0 Hz, 1H), 3.05 (bs,1H), 2.63 (s, 3H), 1.33 (s, 6H), 1.14 (s, 9H). MS (ESI) m/z 377 (M +H)⁺. Anal. calcd. for C₁₉H₂₈N₄O₄ (+0.45 H₂O, 0.30 C₃H₆O, 0.10 C₄H₈O₂HCl): C, 59.35; H, 7.73; N, 13.64; O, 19.28. Found: C, 58.95; H, 7.54;N; 13.61. Example 130N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[(1-hydroxycyclopentyl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, CDCl₃) δ 9.41 (d, J = 7.5 Hz, 1H), 8.18 (d, J = 6.0 Hz,1H), 7.27-7.14 (m, 3H), 5.84 (bs, 1H), 5.50 (bs, 1H), 4.22 (d, J = 7.5Hz, 1H), 4.04 (s, 2H), 1.92-1.66 (m, 8H), 1.14 (s, 9H). MS (ESI) m/z 389(M + H)⁺. Anal. calcd. for C₂₀H₂₈N₄O₄ (+0.30 H₂O): C, 60.99; H, 7.32; N,14.22; O, 17.47. Found: C, 60.62; H, 7.31; N; 13.94. Example 131N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[2-(4-hydroxytetrahydro-2H-pyran-4-yl)ethyl]-4-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (270 MHz, ODCl₃) δ 9.51 (d, J = 9.5 Hz, 1H), 8.11 (d, J = 7.4 Hz,1H), 7.05 (dd, J = 7.4, 7.4 Hz, 1H), 6.97 (d, J = 7.4 Hz, 1H), 5.88 (bs,1H), 5.59 (bs, 1H), 4.30 (m, 2H), 4.22 (d, J = 9.5 Hz, 1H), 3.89-3.67(m, 4H), 2.62 (s, 3H), 2.17 (s, 1H), 1.94 (t, J = 8.1 Hz, 2H), 1.84-1.50(m, 4H), 1.14 (s, 9H). MS (ESI) m/z 433 (M + H)⁺. Example 132N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, CDCl₃) δ 9.45 (d, J = 9.0 Hz, 1H), 8.18 (d, J = 9.0 Hz,1H), 7.25-7.14 (m, 2H), 7.03 (d, J = 9.0 Hz, 1H), 5.98 (bs, 1H), 5.73(bs, 1H), 4.24 J = 9.0 Hz, 1H) 4.05-3.89 (m, 2H), 3.85-3.67 (m, 2H),3.41-3.30 (m, 2H), 2.22-2.08 (m, 1H), 1.68-1.35 (m, 4H), 1.16 (s, 9H).MS (ESI) m/z 389 (M + H)⁺. Example 133N-[(1S)-1-tert-butyl-3,3,3-trifluoro-2-hydroxypropyl]-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide hydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ 10.57 (bs, 1H), 8.87 (d, J = 12.0 Hz, 1H),8.09 (d, J = 9.0 Hz, 1H), 7.50 (d, J = 6.0 Hz, 1H), 7.37-7.16 (m, 2H),6.59 (bs, 1H), 4.51-3.93 (m, 5H), 3.77-3.05 (m, 9H), 1.02 (s, 9H). MS(ESI) m/z 459 (M + H)⁺. Anal. calcd. for C₂₁H₂₉F₃N₄O₄ (+2.1 H₂O, 1.0HCl): C, 47.34; H, 6.47; N, 10.52; O, 18.32; F, 10.70; Cl, 6.65. Found:C, 47.03; H, 6.17; N; 10.19. Example 134N-[(1S)-1-tert-butyl-3,3,3-trifluoro-2-oxopropyl]-3-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, DMSO-d₆) δ 9.52 (d, J = 7.5 Hz, 1H), 7.96 (d, J = 9.0Hz, 1H), 7.44-7.10 (m, 3H), 4.88 (d, J = 7.5 Hz, 1H), 4.04 (t, J = 6.0Hz, 2H), 3.59-3.41 (m, 4H), 2.61 (t, J = 6.0 Hz, 2H), 2.75-2.36 (m, 4H),1.08 (s, 9H). MS (ESI) m/z 457 (M + H)⁺. Anal. calcd. for C₂₁H₂₇F₃N₄O₄(+2.1 H₂O, 1.0 HCl): C, 54.82; H, 6.00; N, 12.18; O, 14.61; F, 12.39.Found: C, 54.51; H, 5.95; N; 11.96. Example 135N-[(1R)-1-(cyanomethyl)-2,2-dimethylpropyl]-3-(3-hydroxy-3-methylbutyl)-2-oxo-2,3-dihydro-1H-benzimdazole-1-carboxamide

¹H-NMR (300 MHz, CDCl₃) δ 9.22 (d, J = 9.0 Hz, 1H), 8.22 (d, J = 9.0 Hz,1H), 7.30-7.08 (m, 3H), 4.23-4.02 (m, 3H), 2.81 (dd, J = 17.3, 6.0 Hz,1H), 2.56 (dd, J = 17.3, 7.5 Hz, 1H), 1.93 (t, J = 7.5 Hz, 2H), 1.34 (s,6H), 1.07 (s, 9H). MS(ESI) m/z 377 (M + H)⁺. Anal. calcd. for C₂₀H₂₈N₄O₃(+1.0 H₂O): C, 61.52; H, 7.74; N, 14.35; O, 16.39. Found: C, 61.83; H,7.47; N; 14.36. Example 136N-[(1R)-1-(2-amino-2-oxoethyl)-2,2-dimethylpropyl]-3-(3-hydroxy-3-methylbutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, CDCl₃) δ 9.08 (d, J = 10.8 Hz, 1H), 8.20 (d, J = 8.1Hz, 1H), 7.41-7.02 (m, 3H), 6.60 (bs, 1H), 5.30 (bs, 1H), 4.22-3.96 (m,3H), 2.72 (dd, J = 11.5, 4.1 Hz, 1H), 2.40 (dd, J = 11.5, 5.4 Hz, 1H),1.92 (t, J = 8.1 Hz, 2H), 1.34 (s, 6H), 1.04 (s, 9H). MS (ESI) m/z 391(M + H)⁺. HR-MS (FAB) Calcd. for C₂₀H₃₁N₄O₄: 391.2345. Found: 391.2343.Example 137N-[(1R)-1-(2-hydroxyethyl)-2,2-dimethylpropyl]-3-(3-hydroxy-3-methylbutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (270 MHz, CDCl₃) δ 8.88 (d, J = 10.8 Hz, 1H), 8.20 (d, J = 5.4Hz, 1H), 7.28-7.05 (m, 3H), 4.11-3.97 (m, 3H), 3.69-3.65 (m, 2H), 3.31(bs, 1H), 2.12-1.98 (m, 1H), 1.92 (t, J = 8.1 Hz, 2H), 1.72-1.68 (m,2H), 1.34 (s, 6H), 1.04 (s, 9H). MS (ESI) m/z 378 (M + H)⁺. Anal. calcd.for C₂₀H₃₁N₃O₄ (+0.8 H₂O): C, 61.30; H, 8.38; N, 10.72; O, 19.60. Found:C, 61.56; H, 8.06; N; 10.73. Example 138N-[(1S)-1-tert-butyl-2-hydroxy-2-methylpropyl]-3-(3-hydroxy-3-methylbutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, CDCl₃) δ 8.25 (d, J = 9.0 Hz, 1H), 7.35-7.04 (m, 4H),4.12-4.07 (m, 2H), 3.84 (d, J = 9.0 Hz, 1H), 1.94 (t, J = 9.0 Hz, 2H),1.70 (s, 1H), 1.68 (s, 1H), 1.42 (s, 3H), 1.39 (s, 3H), 1.35 (s, 6H),1.16 (s, 9H). MS (ESI) m/z 392 (M + H)⁺. Anal. calcd. for C₂₁H₃₃N₃O₄(+0.5 H₂O): C, 62.98; H, 8.56; N, 10.49; O, 17.98. Found: C, 63.02; H,8.38; N; 10.46. Example 139N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(2-dimethylamino)-2-methylprpyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamidehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ 11.07 (bs, 1H), 9.13 (d, J = 9.0 Hz, 1H),8.08 (d, J = 6.0 Hz, 1H), 7.72 (bs, 1H), 7.59 (d, J = 6.0 Hz, 1H),7.41-7.04 (m, 3H), 4.44-4.18 (m, 3H), 2.84 (d, J = 3.0 Hz, 6H), 1.41 (s,6H), 1.41 (s, 6H), 1.00 (s, 9H). MS (ESI) m/z 390 (M + H)⁺. Anal. calcd.for C₂₀H₃₁N₃O₄ (+1.5 H₂O, 1.0 HCl, 0.2 C₄H₈O₂): C, 53.09; H, 7.84; N,14.88; O, 16.66; Cl, 7.53. Found: C, 53.14; H, 7.77; N; 14.53. Example140 N-[(1S)-2,2-dimethyl-1-(1,3,4-oxadiazol-2-yl)propyl]-3-(3-hydroxy-3-methylbutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (270 MHz, CDCl₃) δ 9.69 (d, J = 8.1 Hz, 1H), 8.39 (s, 1H), 8.15(d, J = 8.1 Hz, 1H), 7.35-7.06 (m, 3H), 5.27 (d, J = 8.1 Hz, 1H),4.16-4.03 (m, 2H), 1.96-1.87 (m, 2H), 1.34 (s, 6H), 1.13 (s, 9H). MS(ESI) m/z 402 (M + H)⁺. HR-MS (FAB) Calcd. for C₂₀H₂₈N₅O₄: 402.2141.Found: 402.2150. Example 141N-{(1R)-2,2-dimethyl-1-[(2-methyl-2H-tetrazol-5-yl)methyl]propyl)-3-(3-hydroxy-3-methylbutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carbox-amide

¹H-NMR (300 MHz, CDCl₃) δ 8.95 (d, J = 9.0 Hz, 1H), 8.09 (d, J = 9.0 Hz,1H), 7.36-6.99 (m, 3H), 4.31-4.22 (m, 1H), 4.22 (s, 3H), 4.05 (t, J =7.5 Hz, 2H), 3.31 (dd, J = 15.0, 3.0 Hz, 1H), 2.96 (dd, J = 15.0, 12.0Hz, 1H), 1.91 (t, J = 7.5 Hz, 2H), 1.89 (s, 1H), 1.33 (s, 6H), 1.08 (s,9H). MS (ESI) m/z 430 (M + H)⁺. HR-MS (FAB) Calcd. for C₂₁H₃₂N₇O₃:430.2567. Found: 430.2580. Example 142N-[(1S)-1-tert-butyl-3,3,3-trlfluoro-2-oxopropyl]-3-(3-hydroxy-3-methyl-butyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, CDCl₃) δ 9.53 (d, J = 7.5 Hz, I H), 8.15 (d, J = 6.0Hz, 1H), 7.24-7.02 (m, 3H), 4.90 (d, J = 7.5 Hz, 1H), 4.08 (t, J = 7.5Hz, 2H), 1.93 (t, J = 7.5 Hz, 2H), 1.34 (s, 6H), 1.15 (s, 9H). MS (ESI)m/z 430 (M + H)⁺. HR-MS (FAB) Calcd. for C₂₀H₂₇F₃N₃O₄: 430.1954. Found:430.1962. Example 143N-[(1S)-1-tert-butyl-3,3,3-trifluoro-2-oxopropyl]-3-[2-(methylsulfonyl)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, CDCl₃) δ 9.36 (d, J = 7.5 Hz, 1H), 8.17 (d, J = 9.0 Hz,1H), 7.35-7.16 (m, 3H), 4.91 (d, J = 7.5 Hz, 1H), 4.42 (t, J = 6.8 Hz,2H), 3.50 (t, J = 6.8 Hz, 2H), 2.97 (s, 3H), 1.15 (s, 9H). MS (ESI) m/z450 (M + H)⁺. HR-MS (FAB) Calcd. for C₁₈H₂₃F₃N₃O₅S: 450.1311. Found:450.1326. Example 144N-[2,2-dimethyl-1-(1,3-oxazol-2-yl)propyl]-3-(3-hydroxy-3-methylbutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, CDCl₃) δ 9.65 (d, J = 9.0 Hz, 1H), 8.18 (d, J = 9.0 Hz,1H), 7.62 (s, 1H), 7.27-7.02 (m, 4H), 5.11 (d, J = 9.0 Hz, 1H), 4.08 (t,J = 8.3 1.93 J = 8.3 Hz, 2H), 1.78 (bs, 1H), 1.34 (s, 6H), 1.08 (s, 9H).MS (ESI) m/z 401 (M + H)⁺. HR-MS (FAB) Calcd. for C₂₁H₂₉F₃N₄O₄:401.2189. Found: 401.2189. Example 145N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]-4-methyl]-2-oxo-2,3-dihydro-1H-benzimidarole-1-carboxamide

¹H-NMR (300 MHz, CDCl₃) δ 9.43 (d, J = 9.0 Hz, 1H), 8.16 (d, J = 7.5 Hz,1H), 7.09 (dd, J = 7.5, 7.5 Hz, 1H), 6.98 (d, J = 7.5 Hz, 1H), 5.76 (bs,1H), 5.46 (bs, 1H), 4.25 (s, 2H), 4.20 (d, J = 9.0 Hz, 1H), 3.86-3.71(m, 5H), 2.64 (s, 3H), 1.91-1.70 (m, 2H), 1.60-1.50 (m, 2H), 1.14 (s,9H). MS (ESI) m/z 419 (M + H)⁺. Anal. calcd. for C₂₁H₃₀N₄O₅ (+0.2 H₂O,0.2 C₄H₈O₂, 0.1 C₆H₁₄): C, 58.14; H, 7.62; N, 12.11; 0, 22.13. Found: C,58.40; H, 7.22; N; 12.48. Example 146N-[(1S)-2,2-dimethyl-1-(2-methyl-2H-tetrazol-5-yl)propyl]-3-(3-methoxypropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, CDCl₃) δ 9.71 (d, J = 9.0 Hz, 1H), 8.16 (d, J = 6.0 Hz,1H), 7.23-7.04 (m, 3H), 5.30 (d, J = 9.0 Hz, 1H), 4.34 (s, 3H), 4.02 (t,J = 7.5 Hz, 2H), 3.41 (t, J = 6.0 Hz, 2H), 3.34 (s, 3H), 2.12-1.97 (m,2H), 1.09 (s, 9H). MS (ESI) m/z 402 (M + H)⁺. Example 147N-[(1S)-2,2-dimethyl-1-(2-methyl-2H-tetrazol-5-yl)propyl]-3-(3-hydroxybutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide (1:1)

¹H-NMR (300 MHz, CDCl₃) δ 9.67-9.52 (m, 1H), 8.18 (d, J = 6.0 Hz, 1H),7.32-7.05 (m, 3H), 5.30 (d, J = 9.0 Hz, 1H), 4.39-4.17 (m, 4H),3.97-3.70 (m, 2H), 2.80-2.70 (m, 1H), 1.99-1.65 (m, 2H), 1.29-1.18 (m,3H), 1.09 (s, 9H). MS (ESI) m/z 402 (M + H)⁺. Example 148N-[(1S)-2,2-dimethyl-1-(1,3-oxazol-5-yl)propyl]-3-(3-hydroxy-3-methylbutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, CDCl₃) δ 9.52 (d, J = 9.0 Hz, 1H), 8.18 (d, J = 9.0 Hz,1H), 7.84 (s, 1H), 7.32-7.07 (m, 3H), 7.00 (s, 1H), 5.06 (d, J = 9.0 Hz,1H), 4.09 (t, J = 7.5 Hz, 2H), 1.93 (t, J = 7.5 Hz, 2H), 1.73 (bs, 1H),1.35 (s, 6H), 1.07 (s, 9H). MS (ESI) m/z 401 (M + H)⁺. Example 149N-[(1S)-1-2,2-dimethyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)propyl]-3-(3-hydroxy-3-methylbutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, CDCl₃) δ 9.61 (d, J = 8.7 Hz, 1H), 8.15 (d, J = 7.2 Hz,1H), 7.23-7.14 (m, 2H), 7.09-7.06 (m, 1H), 5.17 (d, J = 8.7 Hz, 1H),4.10-4.05 (m, 2H), 2.54 (s, 3H), 1.95-1.90 (m, 2H), 1.34 (s, 6H), 1.12(s, 9H). MS (ESI) m/z 416 (M + H)⁺. Anal. calcd. for C₂₁H₂₉N₅O₄: C,60.71; H, 7.04; N, 16.86; O, 15.40. Found: C, 60.55; H, 7.04; N, 16.76.

Following Examples 150 to 151 were prepared according to the proceduredescribed in Example 107.

Example 1501-[3-({[2,2-dimethyl-1-(2-methyl-2H-tetrazol-5-yl)propyl]amino}carbonyl)-7-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]-2-methylpropan-2-aminium formate

¹H-NMR (300 MHz, CDCl₃) δ 9.60 (d, J = 9.0 Hz, 1H), 8.34 (s, 1H), 8.17(d, J = 8.3 Hz, 1H), 7.07 (dd, J = 8.3, 8.3 Hz, 1H), 6.97 (d, J = 8.3Hz, 1H), 5.30 (d, J = 9.0 Hz, 1H), 4.33 (bs, 5H), 3.50 (s, 2H), 2.60 (s,3H), 1.43 (s, 3H), 1.40 (s, 3H), 1.07 (s, 9H). MS (ESI) m/z 415 (M +H)⁺. Example 1514-[3-({(2,2-dimethyl-1-(2-methyl-2H-tetrazol-5-yl)propyl]amino}carbonyl)-7-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]-2-methylbutan-2-aminium formate

¹H-NMR (300 MHz, CDCl₃) δ 9.75 (d, J = 9.0 Hz, 1H), 8.40 (s, 1H), 8.10(d, J = 6.0 Hz, 1H), 7.06-6.79 (m, 2H), 5.30 (d, J = 9.0 Hz, 1H),4.34-4.20 (m, 2H), 4.33 (s, 3H), 3.25 (bs, 3H), 2.58 (s, 3H), 2.05 (t, J= 9.0 Hz, 2H), 1.43 (s, 6H), 1.06 (s, 9H). MS (ESI) m/z 429 (M + H)⁺.

Following Examples 152 to 154 were prepared according to the proceduredescribed in Example 102.

Example 152 N-[(1S)-1-aminocarbonyl)-2,2-dimethylpropyl]-4-methyl-3-[2-(methylthio)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole- 1-carboxamide

¹H-NMR (300 MHz, CDCl₃) δ 9.54 (d, J = 8.1 Hz, 1H), 8.11 (d, J = 7.5 Hz,1H), 7.06 (t, J = 7.5 Hz, 1H), 6.97 (d, J = 7.5 Hz, 1H), 5.82 (bs, 1H),5.49 (bs, 1H), 4.33-4.27 (m, 2H), 4.21 (d, J = 8.1 Hz, 1H), 2.85-2.80(m, 2H), 2.59 (s, 3H), 2.22 (s, 3H), 1.14 (s, 9H). MS (ESI) m/z 379 (M +H)⁺. Anal. calcd. for C₁₈H₂₆N₄O₃S: C, 57.12; H, 6.92; N, 14.80; O,12.68; S, 8.47. Found: C, 57.19; H, 6.93; N, 14.78. Example 153N-{(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl}-4-methyl-3-[2-(methylthio)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, CDCl₃) δ 9.56-9.45 (m, 1H), 8.09 (d, J = 7.2 Hz, 1H),7.08-7.03 (m, 1H), 6.96 (d, J = 7.5 Hz, 1H), 5.81 (bs, 1H), 4.32-4.27(m, 2H), 4.14 (d, J = 8.1 Hz, 1H), 2.85-2.79 (m, 5H), 2.59 (s, 3H), 2.22(s, 3H), 1.11 (s, 9H). MS (ESI) m/z 393 (M + H)⁺. Anal. calcd. forC₁₉H₂₈N₄O₃S (+0.2 H₂O): C, 57.61; H, 7.23; N, 14.14; O, 12.92; S, 8.10.Found: C, 57.29; H, 7.21; N, 14.01. Example 154N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]-4-methyl-3-[2-(methylthio)ethyl-2-oxo-2,3-dihydro-1H-benzimidazole- 1-carboxamide

¹H-NMR (300 MHz, DMSO-d₆) δ 8.92 (d, J = 9.6 Hz, 1H), 8.04-8.01 (m, 1H),7.08-7.00 (m, 2H), 4.74-4.66 (m, 1H), 4.27-4.23 (m, 2H), 3.74-3.64 (m,2H), 3.51-3.43 (m, 1H), 2.84-2.79 (m, 2H), 2.59 (s, 1H), 2.15 (s, 3H),0.95 (s, 9H). MS (ESI) m/z 366 (M + H)⁺. Anal. calcd. for C₁₈H₂₇N₃O₃S:C, 59.15; H, 7.45; N, 11.50; O, 13.13; S, 8.77. Found: C, 58.76; H,7.39; N, 11.48.

Following Examples 155 to 161 were prepared according to the proceduredescribed in Example 103.

Example 155 N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-4-methyl-3-[2-(methylsulfonyl)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole- 1-carboxamide

¹H-NMR (300 MHz, CDCl₃) δ 9.41 (d, J = 8.7 Hz, 1H), 8.12 (d, J = 8.7 Hz,1H), 7.12-7.06 (m, 1H), 7.00 (d, J = 8.1 Hz, 1H), 5.75 (bs, 1H), 5.48(bs, 1H), 4.66-4.61 (m, 2H), 4.21 (d, J = 8.7 Hz, 1H), 3.51-3.46 (m,2H), 3.04 (s, 2H), 2.65 (s, 3H), 1.14 (s, 9H). MS (ESI) m/z 411 (M +H)⁺. Anal. calcd. for C₁₈H₂₆N₄O₅S (+0.5 H₂O, 0.2 C₄H₈O₂): C, 51.66; H,6.59; N, 12.82; O, 21.60; S, 7.34. Found: C, 51.96; H, 6.33; N, 12.89.mp 177.5 degrees Celsius, 238.2 degrees Celsius. Example 156N-{(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl}-4-methyl-3-[2-(methylsulfonyl)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, CDCl₃) δ 9.42 (d, J = 9.0 Hz, 1H), 8.09 (d, J = 7.2 Hz,1H), 7.07 (t, J = 7.2 Hz, 1H), 6.98 (d, J = 7.2 Hz, 1H), 5.89-5.80 (m,1H), 4.65-4.57 (m, 2H), 4.16 (d, J = 9.0 Hz, 1H), 3.51-3.46 (m, 2H),3.04 (s, 3H), 2.84 (d, J = 4.5 Hz, 3H), 2.64 (s, 3H), 1.11 (s, 9H). MS(ESI) m/z 425 (M + H)⁺. Anal. calcd. for C₁₉H₂₈N₄O₆S (+0.2 H₂O): C,53.08; H, 6.71; N, 13.03; O, 19.72; Cl, 7.46. Found: C, 52.76; H, 6.54;N, 12.64. Example 157N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]-4-methyl-3-[2-(methylsulfonyl)ethyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHZ, CDCl₃) δ 8.87 (d, J = 9.6 Hz, 1H), 8.02 (dd, J = 7.2,1.2 Hz, 1H), 7.10-7.01 (m, 2H), 4.72-4.69 (m, 1H), 4.53-4.48 (m, 2H),3.74-3.59 (m, 4H), 3.51-3.41 (m, 1H), 3.12 (s, 3H), 2.62 (s, 3H), 0.95(s, 9H). MS (ESI) m/z 398 (M + H)⁺. Anal. calcd. for C₁₈H₂₇N₃O₅S (+0.1H₂O): C, 54.14; H, 6.87; N, 10.52; O, 20.44; S, 8.03. Found: C, 53.90;H, 6.87; N, 10.26. Example 158 rel-N-[(1R,2S)-2-hydroxycyclohexyl]-4-methyl-3-[2-(methylsulfonyl)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, DMSO-d₆) δ 8.80 (d, J = 7.5 Hz, 1H), 8.02-7.99 (m, 1H),7.09-7.01 (m, 2H), 4.87 (d, J = 5.1 Hz, 1H), 4.52-4.47 (m, 2H),3.66-3.45 (m, 3H), 3.11 (s, 3H), 2.61 (s, 3H), 2.10-1.98 (m, 1H),1.92-1.80 (m, 1H), 1.70-1.56 (m, 2H), 1.36-1.20 (m, 4H). MS (ESI) m/z396 (M + H)⁺. Anal. calcd. for C₁₈H₂₅N₃O₅S (+0.3 H₂O): C, 53.93; H,6.44; N, 10.48; O, 21.15; S, 8.00: Found: C, 53.66; H, 6.24; N, 10.36.mp 152.3 degrees Celsius, 238.9 degrees Celsius. Example 159N-[(1S)-2,2-dimethyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)propyl]-3-[2-(methylsulfonyl)ethyl]-2-oxo-2,3-dihydro-1-H-benzimidazole-

¹H-NMR (300 MHz, CDCl₃) δ 9.49 (d, J = 8.1 Hz, 1H), 8.16 (d, J = 8.1 Hz,1H), 7.30-7.15 (m, 3H), 5.17 (d, J = 8.1 Hz, 1H), 4.45-4.40 (m, 2H),3.54-3.49 (m, 2H), 2.98 (S, 3H), 2.41 (s, 3H), 1.12 (s, 9H). MS (ESI)m/z 436 (M + H)⁺. Anal. calcd. for C₁₉H₂₅N₅O₅S: C, 52.40; H, 5.79; N,16.08; O, 18.37; S, 7.36. Found: C, 52.06; H, 5.75; N, 15:79 m.p 124.2degrees Celsius. Example 160N-[(1S)-2,2-dimethyl-1-(2-methyl-2H-tetrazol-5-yl)propyl]-3-[2-(methylsulfonyl)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, CDCl₃) δ 9.56 (d, J = 8.7 Hz, 1H), 8.18 (d, J = 7.5 Hz,1H), 7.28-7.14 (m, 3H), 5.29 (d, J = 8.7 Hz, 1H), 4.44-4.39 (m, 2H),4.34 (s, 3H), 3.54-3.49 (m, 2H), 2.97 (s, 3H), 1.08 (s, 9H). MS (ESI)m/z 436 (M + H)⁺. Anal. calcd. for C₁₈H₂₅N₇O₄S (+0.1 H₂O): C, 49.44; H,5.81; N, 22.42; O, 15.00; S, 7.33. Found: C, 49.18; H, 5.76; N, 22.09.Example 161N-[(1S)-2,2-dimethyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)propyl]-3-[2-(methylsulfonyl)ethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

¹H-NMR (300 MHz, CDCl₃) δ 9.46 (d, J = 10.2 Hz, 1H), 8.18-8.15 (m, 1H),7.30-7.15 (m, 3H), 5.15 (d, J = 10.2 Hz, 1H), 4.45-4.39 (m, 2H),3.54-3.48 (m, 2H), 2.98 (S, 3H), 2.55 (s, 3H), 1.12 (s, 9H). MS (ESI)m/z 436 (M + H)⁺. Anal. calcd. for C₁₉H₂₅N₅O₅S (+0.1 H₂O): C, 52.18; H,5.81; N, 16.02; O, 18.66; S, 7.33. Found: C, 51.91; H, 5.70; N, 15.91.

Example 162 Same as Example 152 Made by Alternative Procedure

N-[(1S)-1-aminocarbonyl)-2,2-dimethylpropyl]-4-methyl-3-[2-(methylthio)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamideSTEP 1: 2-methyl-N-[2-(methylthio)ethyl]-6-nitroaniline

A mixture of 2-chloro-3-nitrotoluene (1.3 g, 7.3 mmol),2-(methylthio)ethylamine (1.4 mL, 15 mmol) and N,N-diisopropylethylamine(5.0 mL, 29 mmol) in 1-methyl-2-pyrrolidinone (3.7 mL) was heated at 220degrees Celsius by microwave for 1 h. The mixture was diluted with ethylacetate (0.10 L) and washed with water (2×50 mL), brine (50 mL), driedover sodium sulfate, filtered, and concentrated to give a crudematerial. The another batch starting from 1.3 g of2-chloro-3-nitrotoluene was combined to this crude material and thecombined crude materials were purified by column chromatography onsilica gel eluting with hexane/ethyl acetate (3/1) to afford 2.6 g (77%)of the title compound: MS (ESI) m/z 227 (M+H)⁺.

STEP 2:7-methyl-1-[2-(methylthio)ethyl]-1,3-dihydro-2H-benzimidazol-2-one

To a solution of 2-methyl-N-[2-(methylthio)ethyl]-nitroaniline (2.6 g,12 mmol) in ethanol (6.0 mL) was added a solution of Tin(II) chloridedihydrate (7.9 g, 35 mmol) In concd. hydrochloric acid (8.0 mL) at 0degrees Celsius and then warmed to room temperature. After 4 hours, thereaction was quenched by addition of 6N sodium hydroxide (100 mL) andextracted with ethyl acetate (100 mL×2), dried over sodium sulfate,filtered, and concentrated. The crude material was dissolved in THF (50mL) and to this solution was added CDI (2.3 g, 14 mmol) and the mixturewas stirred at room temperature. After 12 hours, to the mixture wasadded CDI (1.5 g, 6.7 mmol) and the reaction mixture was refluxed for 5hours. Then the mixture was cooled to room temperature and evaporated todryness. To this residue was added water (100 mL) at 0 degrees Celsiusand extracted with ethyl acetate (100 mL×2). The combined organic layerswere washed with water (50 mL), brine (50 mL), dried over sodiumsulfate, filtered, and concentrated. The obtained material was dissolvedin methanol (30 mL) and to this solution was added 2N sodium hydroxide(3 mL) and stirred at room temperature for 2 hours. Then the mixture wasquenched by addition of sat. aq. sodium bicarbonate (50 mL) andextracted with ethyl acetate (100 mL×2). The combined organic layerswere washed with water (50 mL), brine (50 mL), dried over sodiumsulfate, filtered and concentrated. The residue was purified by columnchromatography on silica gel eluting with dichloromethane/methanol(20/1-10/1) to afford 1.8 g (69%) of the title compound: 6 MS (ESI) m/z223 (M+H)⁺.

STEP 3:N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-4-methyl-3-[2-(methylthio)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

To a solution of7-methyl-1-[2-(methylthio)ethyl]-1,3-dihydro-2H-benzimidazol-2-one (0.22g, 1.00 mmol) in 1,2-dichloroethane (5 mL) were added triethylamine (0.5mL, 3.3 mmol) and 4-nitrophenyl chloroformate (0.24 g, 1.2 mmol) at 0degrees Celsius and the mixture was stirred at room temperature for 4hours. Then to this mixture was added a solution of tert-leucinamide(156 mg, 1.2 mmol) in 1,2-dichloroethane (3 mL) at 0 degrees Celsius andstirred at room temperature. After 14 hours, the reaction was quenchedby addition of water (50 mL) and extracted with dichloromethane (50mL×2). The combined organic layers were washed with water (30 mL×4),brine (30 mL), dried over sodium sulfate, filtered, and concentrated invacuo. The residue was purified by column chromatography on silica geleluting with dichloromethane/methanol (10/1) to afford 0.33 g (87%) ofthe title compound: ¹H-NMR (300 MHz, CDCl₃)

9.54 (d, J=8.1 Hz, 1H), 8.11 (d, J=7.5 Hz, 1H), 7.06 (t, J=7.5 Hz, 1H),6.97 (d, J=7.5 Hz, 1H), 5.82 (bs, 1H), 5.49 (bs, 1H), 4.33-4.27 (m, 2H),4.21 (d, J=8.1 Hz, 1H), 2.85-2.80 (m, 2H), 2.59 (s, 3H), 2.22 (s, 3H),1.14 (s, 9H); MS (ESI) m/z 379 (M+H)⁺.

Anal. calcd. for C₁₈H₂₆N₄O₃S: C, 57.12; H, 6.92; N, 14.80; O, 12.68; S,8.47. Found: C, 57.19; H, 6.93; N, 14.78

The tert-Leucinamide reagent used in step 3 above was prepared in twosteps as follows:

STEP 1: Benzyl [(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]carbamate

To a solution of N-[(benzyloxy)carbonyl]-tert-leucine (preparedaccording to the procedure in the literature; Emily, M. S. et al.Tetrahedron 2001, 57, 5303-5320.; 3.7 g, 14 mmol) in DMF (80 mL) wereadded ammonium chloride (900 mg, 17 mmol), triethylamine (5.9 mL, 42mmol), HOBt (2.8 g, 18 mmol), and EDC (3.1 g, 18 mmol) at rt. After 17h, the reaction mixture was quenched by addition of sat. aq. sodiumbicarbonate (100 mL) and extracted with ethyl acetate (100 mL×3). Thecombined organic layers were washed with water (100 mL×3), brine (50mL), dried over sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel eluting withhexane/ethyl acetate (2/1-1/1) to afford 3.0 g (82%) of the titlecompound.

MS (ESI) m/z 265 (M+H)⁺.

STEP 2: tert-Leucinamide

To a solution of benzyl[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]carbamate (3.7 g, 14 mmol) inTHF (40 mL) was added 10% Pd/C (710 mg). The flask was evacuated andflushed with H₂ gas and this process was repeated three times. The flaskwas filled with H₂ gas (4 atm) and stirred for 3 hours at roomtemperature. Then the reaction mixture was filtered through a pad ofCelite and concentrated in vacuo to give the title compound as whitesolid (crude; 1.8 g):

¹H-NMR (300 MHz, DMSO-d₆)

6.59 (bs, 1H), 5.92 (bs, 1H), 3.12 (s, 1H), 1.02 (s, 1H); MS (ESI) m/z131 (M+H)⁺.

Example 163

N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclohexylmethyl)-5-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide(PF-04431715-51) Step 1: Preparation ofN-(cyclohexylmethyl)-5-methyl-2-nitroaniline

A mixture of cyclohexylmethylamine (1.6 g, 14.2 mmol),3-fluoro-4-nitrotoluene (2.0 g, 13.0 mmol) and N,N-diisopropylethylamine(1.83 g, 14.2 mmol) was heated to 80 degrees Celsius in acetonitrile (10mL) for 2 hours. The reaction was cooled to ambient temperature andpartitioned between water and ethyl acetate. The layers were separatedand aqueous extracted with ethyl acetate (1×30 mL). The organic layerswere combined, dried over sodium sulfate and concentrated in vacuo.Purification of the residue by silica gel chromatography eluting fromexample 1 from 4-[(2-aminophenyl)amino]-2-methyl-2-butanol.

MS (ESI) m/z 221 (M+H)⁺.

STEP 6.N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(3-hydroxy-3-methylbutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

To a solution of1-(3-hydroxy-3-methylbutyl)-1,3-dihydro-2H-benzimidazol-2-one (0.25 g,1.1 mmol) in 1,2-dichloroethane (30 mL) were added triethylamine (0.52mL, 3.7 mmol) and 4-nitrophenyl chloroformate (0.27 g, 1.4 mmol) at 0degrees Celsius and the mixture was stirred for 4 hours at roomtemperature. Then to this mixture was added a mixture ofL-tert-leucinamide (0.18 g, 1.4 mmol) in 1,2-dichloroethane (5 mL) at 0degrees Celsius and stirred at room temperature. After 14 hours, thereaction was quenched by addition of water (50 mL) and filtered andwashed with water (30 mL) and dichloromethane (30 mL). The obtainedsolid was suspended in water (50 mL) and filtered. This procedure wasrepeated twice followed by recrystallization from methanol. The obtainedsolid was suspended in water (50 mL) again and filtered and thisprocedure was repeated twice. Then the solid was dissolved inmethanol/dichloromethane and filtered and concentrated in vacuo. Theobtained solid was then recrystallized from acetone to give 0.14 g (33%)of the title compound.

¹H-NMR (300 MHz, DMSO-d₆) δ 9.21 (d, J=9.0 Hz, 1H), 8.03 (d, J=7.2 Hz,1H), 7.65 (bs, 1H), 7.25-7.12 (m, 4H), 4.50 (s, 1H), 4.33 (d, J=9.0 Hz,1H), 3.96-3.93 (m, 2H), 1.77-1.71 (m, 2H), 1.17 (s, 6H), 0.98 (s, 9H).

MS (ESI) m/z 377 (M+H)⁺.

Anal. calcd. for C₁₉H₂₈N₄O₄: C, 60.62; H, 7.50; N, 14.88; O, 17.00.Found: C, 60.46; H, 7.51; N, 14.59.

mp 247.7 degrees Celsius

[α]_(D) ²³+29.1 (c 0.11, methanol).

>99% ee

Example 102N-{(1S)-1-[(dimethylamino)carbonyl]-2,2-dimethylpropyl}-4-methyl-3-[2-(methylthio)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide

STEP 1. 2-methyl-N-[2-(methylthio)ethyl]-6-nitroaniline

A mixture of 2-chloro-3-nitrotoluene (1.3 g, 7.3 mmol),2-(methylthio)ethylamine (1.4 mL, 15 mmol) and N,N-diisopropylethylamine(5.0 mL, 29 mmol) in 1-methyl-2-pyrrolidinone (3.7 mL) was heated to 220degrees Celsius by microwave for 1 h. The mixture was diluted with ethyl0-10% ethyl acetate/hexanes gave 3.2 g of oil: ¹H NMR (400 MHz, DMSO-d₆)δ 0.92-1.05 (m, 2H), 1.10-1.24 (m, 3H), 1.58-1.72 (m, 6H), 2.27 (s, 3H),3.16 (t, J=6.0 Hz, 2H), 6.45 (dd, J=8.8, 1.2 Hz, 1H), 6.82 (s, 1H), 7.91(d, J=8.4 Hz, 1H), 8.15 (t, J=5.2 Hz, 1H); MS (APES) m/z 249 (M+H).

Step 2: Preparation of1-(cyclohexylmethyl)-6-methyl-1-dihydro-2H-benzimidazol-2-one

A solution of N-(cyclohexylmethyl)-5-methyl-2-nitroaniline (3.2 g, 13mmol) in ethanol (6.5 ml) and concentrated hydrochloric acid (8.7 mL)was added tin(II) chloride dehydrate (8.8 g, 39 mmol) as a solid at 0degrees Celsius. The reaction mixture was allowed to warm to roomtemperature for 2 hours. The mixture was quenched by the addition of 6 NNaOH (100 mL) and extracted with ethyl acetate (3×100 mL). The organiclayers were combined, dried over Na₂SO₄ and concentrated in vacuo. Theresultant orange oil was dissolved in tetrahydrofuran (50 mL) and1,1′-carbonyldiimidazole (2.5 g, 15.6 mmol) was added as a solid. Theresultant mixture was stirred at room temperature overnight. The mixturewas concentrated in vacuo and the residue was partitioned between waterand ethyl acetate. The organic layer was dried over sodium sulfate andevaporated. Purification of the residue by chromatography over silicagel by eluting with 0-10% methanol/dichloromethane gave a yellowmaterial, which was triturated with ethyl acetate and ether to yield2.37 g of white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 0.92-0.99 (m, 2 H),1.05-1.15 (m, 3H), 1.50-1.63 (m, 5H), 1.73 (m, 1H), 2.82 (s, 3H), 3.53(d, J=7.6 Hz, 2H), 6.73 (d, J=8.0 Hz, 1H), 6.80 (d, J=7.6 Hz, 1H), 6.88(s, 1H), 10.61 (s, 1H); MS (APES) m/z 245 (M+H).

Step 3: Preparation ofN-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclohexylmethyl)-5-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide(PF-04431715-51)

To a solution of1-(cyclohexylmethyl)-6-methyl-13-dihydro-2H-benzimidazol-2-one (125 mg,0.51 mmol) in 1,2-dichloroethane (3 mL) was added triethylamine (171 mg,1.7 mmol) and 4-nitrophenylchloroformate (124 mg, 0.61 mmol) at 0degrees Celsius. The reaction mixture was then allowed to warm to roomtemperature and stirred for 4 hours. Tert-leucinamide (80 mg, 0.61 mmol)was added to the reaction mixture and the stirring was continued at roomtemperature overnight. The reaction was quenched by the addition ofwater and the organic layer was washed with water (3×3 mL), dried oversodium sulfate, and concentrated to dryness. To a solution of theresidue in methanol (2 mL) was added trifluoroacetic acid dropwise toyield a white solid, which was collected by filtration to give 82.3 mgof the title compound as a trifluoroacetate salt: ¹H NMR (400 MHz,DMSO-d₆) δ 0.90-1.09 (m, 12H), 1.17 (m, 3H), 1.58-1.70 (m, 5H), 1.83 (m,1H), 2.37 (s, 3H), 3.71 (dd, J=8.0, 4.0 Hz, 2H), 4.23 (d, J=8.78 Hz,1H), 6.95 (d, J=8.05 Hz, 1H), 7.14 (d, J=5.49 Hz, 2H), 7.62 (br. s.,1H), 7.91 (d, J=8.0 Hz, 1H), 9.16 (d, J=9.15 Hz, 1H); MS (ES+) m/z401.255 (M+H).

Example 164

N-[(1S)-1-(5-amino-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropyl]-5-fluoro-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamideStep 1: ((S)-1-Hydrazinocarbonyl-2,2-dimethylpropyl)carbamic acidtert-butyl ester

To a solution of N-Boc-L-tert-leucine (2.0 g, 8.647 mmol) in dry THF (20ml), N,N-carbonyl diimidazole (CDI) (1.54 g, 9.511 mmol) was added andstirred at rt under nitrogen atmosphere for 1.5 h. Hydrazine hydrate(1.3 ml, 26.6 mmol) was then added to it and stirring was continued for18 h at rt. On completion of reaction (monitored by TLC, R_(f)=0.3;solvent system 40% ethyl acetate in hexane), THF was evaporated up todryness and the residual mass dissolved in 1,4-dioxane (50 ml) andfiltered. The filtrate was concentrated under reduced pressure and theresidual mass (as white sticky material) was again dissolved in DCM. Thesolution was washed with distilled water, brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford desired product((S)-1-hydrazinocarbonyl-2,2-dimethylpropyl)carbamic acid tert-butylester (2.3 g) as gummy sticky mass contaminated with imidazole.

¹H NMR (400 MHz, DMSO-d₆) δ: 0.87 (s, 9H), 1.37 (s, 9H), 3.80 (d, J=9.6Hz, 1H), 6.35 (d, J=9.6 Hz, 1H), 9.10 (s, 1H)+imidazole: 7.01 (s, 2H),7.63 (s, 1H). ¹H NMR (400 MHz, DMSO-d₆-D₂O exchange) δ: 0.88 (s, 9H),1.35 (s, 9H), 3.77 (s, (1H), +imidazole: 7.01 (2H, 7.65 (s, 1H). FIA-MS:246.3 [M+H]⁺, 268.3 [M+H+Na]⁺.

Step 2

[1-(5 Amino-[1,3,4]oxadiazol-2-yl)-(S)-2,2-dimethylpropyl]carbamic acidtert-butyl ester: To a clear solution of((S)-1-hydrazinocarbonyl-2,2-dimethylpropyl)carbamic acid tert-butylester (1.5 g, 6.117 mmol) in 1,4-dioxane (50 ml), a solution of NaHCO₃(0.515 g, 6.117 mmol) in distilled water (15 ml) was added to form awhite suspension. Cyanogen bromide (0.65 g, 6.117 mmol) was addedportion wise to the reaction mixture and stirred for 18 h at rt. Oncompletion of reaction (monitored by TLC, R_(f)=0.5; solvent system 50%ethyl acetate in hexane), the dioxane was evaporated under reducedpressure and ethyl acetate (100 ml) was added. This solution was thenwashed twice with distilled water (2×100 ml), brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residualmass obtained was washed with hexane to afford desired product[1-(5-amino-[1,3,4]oxadiazol-2-yl)-(S)-2,2-dimethylpropyl]carbamic acidtert-butyl ester (0.7 g, yield 42%) as off white solid.

¹H NMR (400 MHz, CDCl₃) δ: 1.01 (s, 9H), 1.27 (s, 9H), 4.65 (d, J=9.6Hz, 1H), 5.44 (d, J=8.4 Hz, 1H), 8.92 (br s, 2H). LC-MS (10%-90%CH₃CN-0.05% TFA-water gradient over 5 minutes: 3.30 min, 271.4 [M+H]⁺.

Step 3

5-((S)-1-Amino-2,2-dimethylpropyl)-[1,3,4]oxadiazol-2-ylaminedihydrochloride:[1-(5-Amino-[1,3,4]oxadiazol-2-yl)-(S)-2,2-dimethylpropyl]carbamic acidtert-butyl ester (4.0 g, 14.81 mmol) was dissolved in 75 ml of 4N1,4-dioxane-HCl solution and stirred at rt under nitrogen atmosphere for4 hr. Evaporation of dioxane under reduced pressure gave5-((S)-1-amino-2,2-dimethylpropyl)-[1,3,4]oxadiazol-2-yl aminedihydrochloride as white solid (3.5 g, yield 98.59%).

¹H NMR (400 MHz, DMSO-d₆) δ: 0.95 (s, 9H), 4.31 (d, J=5.6 Hz, 1H), 6.34(br s, 3H), 7.60 (br s, 1H), 8.86 (d, J=4.0 Hz, 3H). LC-MS (10%-90%CH₃CN-0.05% TFA-water gradient over 5 minutes: 0.69 min, 171.1 [M+H]⁺.

Step 4

N-[(1S)-1-(5-amino-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropyl]-5-fluoro-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide(PF-04676113-00)

To a solution of6-fluoro-1-(tetrahydro-2H-pyran-4-ylmethyl)-1,3-dihydro-2H-benzimidazol-2-one(45 mg, 0.18 mmol) in 1,2-dichloroethane (3 ml) was added triethylamine(100 μl, 73 mg, 0.72 mmol) and phosgene as a 1.8 M solution in toluene(120 μl, 21.3 mg, 0.22 mmol) at ambient temperature. The resultantmixture was stirred for 1 hour at ambient temperature (the mixtureturned brown). To this mixture was added5-[(1S)-1-amino-2,2-dimethylpropyl]-1,3,4-oxadiazol-2-aminehydrochloride (44.6 mg, 0.22 mmol) as a solid. The resultant reactionmixture was stirred at 45° C. overnight. The reaction mixture was cooledto ambient temperature and extracted 3×2 ml water. The organic layer wasconcentrated, dissolved in 1 ml DMSO and purified by reversed phase HPLC(acetonitrile/water). 23.5 mg, 29% yield.

¹H NMR (400 MHz, DMSO-d₆) □ ppm 1.03 (s, 8H) 1.32 (dd, J=12.44, 4.03 Hz,2H) 1.54 (d, J=12.44 Hz, 2H) 2.05 (td, J=11.80, 4.57 Hz, 1H) 3.18-3.26(m, 3H) 3.74 (d, J=6.95 Hz, 1H) 3.79 (d, J=7.32 Hz, 2H) 3.81 (br. s.,3H) 4.87 (d, J=8.78 Hz, 1H) 7.03 (s, 2H) 7.11 (td, J=9.15, 2.56 Hz, 1H)7.41 (dd, J=8.78, 4.76 Hz, 1H) 7.79 (dd, J=9.52, 2.56 Hz, 1H) 9.38 (d,J=8.78 Hz, 1H). LC/MS 446.2 (M).

Examples 165-175 were prepared according to the procedures described forExamples 162, 163 and 164.

Structure 1H NMR (400 MHz, Example No. chemical name DMSO-d6) δ ppm Mass(M) 165

0.93-1.60 (m, 12H), 1.15 (m, 3H), 1.64 (m, 5H), 1.81 (m, 1 H), 3.72 (d,J = 4.76 Hz, 2H), 4.24 (d, J = 9.15 Hz, 1H), 7.15 (br. s., 1H), 7.08(dt, J = 8.0, 4.0 Hz, 1H), 7.33 (d, J = 8.60, 4.57 Hz, 1H), 7.63 (br.s., 1H), 7.81 (dd, J = 8.0, 4.0 Hz, 1H), 9.16 (d, J = 8.78 Hz, 1H) 404166

0.93-1.15 (m, 13H), 1.59 (m, 4H), 1.77 (m, 2H), 3.69 (dd, J = 7.2, 2.4Hz, 2H), 4.21 (d, J = 9.2 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1 H), 7.18 (br.s., 1H), 7.26 (dd, J = 8.4, 2.0 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.64(s, 1H), 8.01 (d, J = 2.0 Hz, 1H), 8.09 (d, J = 9.2 Hz, 1H), 9.11 (d, J= 9.2 Hz, 1H) 420 167

0.92-1.07 (m, 12H), 1.14 (m, 3H), 1.58-1.70 (m, 5H), 1.81 (m, 1H), 2.35(s, 3H), 3.70 (dd, J = 8.0, 4.0 Hz, 2H), 4.23 (d, J = 8.78 Hz, 1H), 7.04(d, J = 7.69 Hz, 1H), 7.19 (d, J = 7.69 Hz, 1H), 7.13 (br. s., 1H), 7.62(br. s., 1 H), 7.88 (s, 1H), 9.20 (d, J = 8.78 Hz, 1H) 400 168

0.94-1.07 (m, 12H), 1.16 (m, 3H), 1.58-1.70 (m, 5H), 1.81 (m, 1H), 3.77(d, J = 6.95 Hz, 2H), 4.27 (d, J = 8.79 Hz, 1H), 7.18 (br. s., 1 H),7.54 (d, J = 8.42 Hz, 1H), 7.72 (d, J = 8.05 Hz, 1H), 7.66 (br. s., 1H),8.30 (s, 1 H), 9.05 (d, J = 9.15 Hz, 1H) 411 169

0.89-1.03 (m, 9H), 1.10-1.16 (m, 3H), 1.57-1.62 (m, 4H), 1.78 (m, 1H),3.68 (dd, J = 7.2, 2.0 Hz, 2 H), 4.21 (d, J = 9.2 Hz, 2H), 6.87-6.96 (m,2H), 7.19 (s, 1 H), 7.32 (dd, J = 8.8, 2.4 Hz, 1H), 7.63 (s, 1H), 7.96(m, 1H), 8.08 (d, J = 9.2 Hz, 1 H), 9.07 (d, J = 9.2 Hz, 1H) 404 170

0.89-1.16 (m, 12H), 1.62 (m, 4H), 1.78 (m, 1H), 3.70 (d, J = 7.6 Hz,2H), 4.21 (d, J = 8.8 Hz, 1H), 6.91 (dd, , J = 6.8, 2,0 Hz, 1 H), 7.16(m, 2H), 7.50 (s, 1H), 7.63 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 8.09 (d,J = 9.2 Hz, 1H), 9.09 (d, J = 8.8 Hz, 1H) 420 171

0.90-1.09 (m, 11H), 1.16 (m, 3H), 1.58-1.70 (m, 5H), 1.84 (m, 1H), 3.75(d, J = 7.32 Hz, 2H), 4.26 (d, J = 8.79 Hz, 1H), 7.17 (br. s., 1 H),7.64 (br. s., 1H), 7.61 (d, J = 8.42 Hz, 1H), 7.93 (s, 1H), 8.16 (d, J =8.05 Hz, 1H), 9.11 (d, J = 8.79 Hz, 1H) 411 172

0.89-1.16 (m, 13H), 1.58-1.73 (m, 6H), 3.75 (m, 2H), 4.21 (d, J = 9.2Hz, 1H), 6.89 (d, J = 9.2 Hz, 1H), 7.12 (m, 2H), 7.18 (s, 1H), 7.64 (s,1H), 7.89 (d, J = 8.8 Hz, 1 H), 8.08 (d, J = 8.8 Hz, 1H), 9.14 (d, J =8.8 Hz, 1H) 404 173

0.89-1.11 (m, 13H), 1.58-1.63 (m, 5H), 1.79 (m, 1H), 3.96 (dt, J = 7.2,1.6 Hz, 2 H), 4.21 (d, J = 9.2 Hz, 2H), 7.13 (t, J = 8.0 Hz, 1H), 7.18(s, 1H), 7.23 (dd, J = 8.0, 1.2, 1H), 7.64 (s, 1 H), 8.08 (dd, J = 8.0,1.2 Hz, 1H), 9.18 (d, J = 8.8 Hz, 1H) 420 174

0.93-1.00 (m, 12H), 1.17 (m, 3H), 1.60 (m, 3H), 1.68 (m, 2 H), 2.57 (s,3H), 3.89 (d, J = 6.95 Hz, 2H), 4.25 (d, J = 8.78 Hz, 1H), 7.08-6.98 (m,1 H), 7.02 (d, J = 4.76 Hz, 1H), 7.13 (br. s., 1H), 7.62 (s, 1H), 8.00(d, J = 7.69 Hz, 1H), 9.31 (d, J = 8.78 Hz, 1H) 400 175

0.93-1.12 (m, 11H), 1.17 (m, 4H), 1.63 (m, 1H), 1.71 (d, J = 8.8 Hz,4H), 1.86 (m, 1H), 3.95 (d, J = 7.32 Hz, 2H), 4.26 (d, J = 9.15 Hz, 1H),7.18 (s, 1H), 7.30 (t, J = 8.05 Hz, 1H), 7.67-7.62 (m, 1H), 8.37 (d, J =8.0 Hz, 1H), 9.08 (d, J = 8.8 Hz, 1H) 411

Examples 176-379 can be prepared according to the procedures describedabove.

Example Structure Mass Number Chemical Name NMR Date (M) 176

1H NMR (400 MHz, DMSO-d6) δ ppm 8.82 (1H, d, J = 9.5 Hz), 8.07 (1H, d, J= 8.1 Hz), 7.32 (1H, d, J = 7.7 Hz), 7.22 (1H, t, J = 7.7 Hz), 7.14 (1H,t, J = 7.7 Hz), 3.73 (2H, dd, J = 6.8, 4.6 Hz), 3.69 (1H, br. s.), 3.66(1H, d, J = 4.8 Hz), 3.48 (1H, dd, J = 11.3, 4.8 Hz), 1.82 (1H, dd, J =8.1, 7.0 Hz), 1.63 (5H, d, J = 15.7 Hz), 1.23 (1H, br. s.), 1.15 (3H, d,J = 7.7 Hz), 1.04 (2H, d, J = 11.3 Hz), 1.08 (1H, br. s.), 0.95 (10H, s)373.2 177

1H NMR (400 MHz, DMSO-d6) δ ppm 8.83 (1H, d, J = 9.1 Hz), 8.06 (1H, d, J= 7.7 Hz), 7.34 (1H, d, J = 7.7 Hz), 7.22 (1H, t, J = 7.7 Hz), 7.14 (1H,t, J = 7.7 Hz), 4.65 (1H, t, J = 5.3 Hz), 3.94 (2H, dd, J = 7.0, 4.4Hz), 3.64- 3.74 (2H, m), 3.44-3.51 (1H, m), 1.98 (2H, d, J = 5.5 Hz),1.83 (3H, t, J = 10.4 Hz), 0.96 (9H, s) 345.2 178

1H NMR (400 MHz, DMSO-d6) δ ppm 8.83 (1H, d, J = 9.5 Hz), 8.07 (1H, d, J= 7.7 Hz), 7.32 (1H, d, J = 8.1 Hz), 7.23 (1H, t, J = 7.3 Hz), 7.15 (1H,t, J = 7.7 Hz), 4.66 (1H, t), 3.84-3.93 (2 H, m), 3.89 (0H, d, J = 11.7Hz), 3.63- 3.74 (2H, m), 3.43-3.52 (1H, m), 3.21 (0H, br. s.), 1.64-1.74(2H, m), 1.70 (0H, d, J = 6.6 Hz), 1.22-1.37 (4 H, m), 0.95 (10H, s),0.86 (3H, t, J = 66 Hz) 347.2 179

1H NMR (400 MHz, DMSO-d6) δ ppm 9.02 (1H, br. s.), 8.11 (1H, d, J = 9.2Hz), 8.04 (1H, d, J = 7.7 Hz), 7.33 (1H, d, J = 7.7 Hz), 7.24 (1H, t, J= 7.3 Hz), 7.16 (1H, t, J = 7.5 Hz), 6.93 (1H, d, J = 9.2 Hz), 3.74 (3H,d, J = 7.3 Hz), 3.67 (2H, br. s.), 3.58 (1H, d, J = 5.9 Hz), 3.42 (1H,d, J = 4.4 Hz), 3.41 (1H, d, J = 18.7 Hz), 3.31 (1H, br. s.), 3.12 (1H,d, J = 4.4 Hz), 3.07-3.16 (1H, m), 2.18 (1H, d, J = 5.9 Hz), 1.99 (1H,d, J = 8.8 Hz), 1.79-1.87 (2H, m), 1.66 (5H, br. s.), 1.24 (3H, t, J =7.1 Hz), 1.15 (3H, d, J = 7.3 Hz), 1.04 (1H, d, J = 11.7 Hz) 384.3 180

1H NMR (400 MHz, DMSO-d6) δ ppm 9.02 (1H, br. s.), 8.03 (1H, d, J = 8.1Hz), 7.34 (1H, d, J = 8.1 Hz), 7.24 (1H, t, J = 7.7 Hz), 7.16 (1H, t, J= 7.7 Hz), 3.94 (2H, d, J = 7.0 Hz), 3.63 (1H, br. s.), 3.69 (2H, d, J =14.3 Hz), 3.58 (1 H, br. s.), 3.42 (1H, br. s.), 3.11 (2H, br. s.), 2.77(1H, dt, J = 14.9, 7.4 Hz), 2.18 (1H, br. s.), 1.93-2.00 (1H, m), 1.98(2H, d, J = 7.0 Hz), 1.83 (5H, t, J = 10.2 Hz), 1.88 (1H, br. s.), 1.24(3 H, t, J = 7.0 Hz) 356.2 181

1H NMR (400 MHz, DMSO-d6) δ ppm 8.83 (1H, d, J = 4.4 Hz), 8.08 (1H, dd,J = 19.6, 8.6 Hz), 7.27-7.32 (1H, m), 7.23 (1H, q, J = 7.8 Hz), 7.14(1H, t, J = 7.7 Hz), 6.91 (1H, d, J = 9.1 Hz), 3.88 (2H, t, J = 6.8 Hz),3.45 (1H, td, J = 6.6, 3.3 Hz), 3.09 (1H, dt, J = 9.2, 4.7 Hz), 2.82(1H, dd, J = 12.1, 7.3 Hz), 2.63 (1H, d, J = 4.8 Hz), 2.26 (1H, dd, J =11.9, 6.8 Hz), 2.16 (1H, q, J = 8.4 Hz), 1.85 (1H, dd, J = 11.9, 8.2Hz), 1.70 (1H, br. s.), 1.67 (3H, d, J = 7.3 Hz), 1.54 (1H, dd, J =12.1, 6.2 Hz), 1.30 (3H, d, J = 7.0 Hz), 1.24- 1.33 (1H, m), 1.05 (3H,t, J = 7.1 Hz), 0.85 (3H, t, J = 6.6 Hz) 358.2 182

1H NMR (400 MHz, DMSO-d6) δ ppm 8.91 (1H, t, J = 6.0 Hz), 8.04 (1H, d, J= 8.1 Hz), 7.33 (1H, d, J = 7.7 Hz), 7.24 (1H, t, J = 7.5 Hz), 7.16 (1H,t, J = 7.7 Hz), 3.73 (2H, d, J = 7.0 Hz), 3.35 (5H, d, J = 6.2 Hz), 3.00(2H, br. s.), 2.82 (5H, br. s.), 1.81 (1H, br. s.), 1.64 (5H, d, J =14.6 Hz), 1.24 (1H, br. s.), 1.15 (3H, d, J = 6.6 Hz), 1.05 (8H, br. s.)387.3 (M + H) 183

1H NMR (400 MHz, DMSO-d6) δ ppm 0.90 (br. s., 6H) 1.83 (br. s., 4H) 1.98(d, J = 6.22 Hz, 2H) 2.16 (br. s., 1 H) 2.26 (br. s., 6H) 3.31 (br. s.,2H) 3.94 (br. s., 3H) 7.08-7.26 (m, 3H) 7.33 (d, J = 7.69 Hz, 1H) 8.04(d, J = 6.96 Hz, 1H) 9.01 (br. s., 1H) 358.2 184

1H NMR (400 MHz, DMSO-d6) δ ppm 8.99 (1H, t, J = 4.9 Hz), 8.05 (1H, d, J= 8.1 Hz), 7.28-7.33 (1H, m), 7.23 (1H, t, J = 7.7 Hz), 7.14 (1H, t, J =7.7 Hz), 6.93 (1H, d, J = 9.1 Hz), 3.88 (2H, t, J = 7.1 Hz), 3.23-3.24(1H, m), 2.27 (6H, s), 2.18 (2H, s), 2.02 (1H, s), 1.88 (1H, s), 1.83(1H, s), 1.69 (2H, t, J = 7.0 Hz), 1.30 (2H, d, J = 3.3 Hz), 1.24-1.34(2H, m), 0.90 (6H, s), 0.85 (3H, t, J = 6.8 Hz) 360.3 185

1H NMR (400 MHz, DMSO-d6) δ ppm 8.78 (1H, d, J = 8.1 Hz), 8.61 (1 H, dd,J = 10.4, 4.2 Hz), 8.05 (1H, d, J = 8.1 Hz), 7.30-7.36 (1H, m), 7.25(1H, t, J = 7.7 Hz), 7.17 (1H, t, J = 7.7 Hz), 4.43 (1H, d, J = 4.4 Hz),3.73 (2H, d, J = 7.0 Hz), 3.17 (3H, br. s.), 2.95 (1 H, br. s.), 1.81(1H, br. s.), 1.60-1.70 (5H, m), 1.30 (3H, d, J = 6.2 Hz), 1.23 (6H, d,J = 6.2 Hz), 1.15 (3H, d, J = 6.2 Hz), 1.04 (2H, d, J = 8.4 Hz), 1.08(1H, br. s.) 386.3 186

1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 (1H, d, J = 6.6 Hz), 7.33 (1 H, d,J = 8.1 Hz), 7.15 (1H, d, J = 8.4 Hz), 7.22 (1H, t, J = 7.3 Hz), 4.01(1H, br. s.), 3.92 (3H, d, J = 7.0 Hz), 3.30 (3 H, br. s.), 2.77 (1H, d,J = 6.2 Hz), 2.62 (2H, dd, J = 10.4, 5.7 Hz), 2.65 (1H, br. s.), 2.58(1H, br. s.), 1.98 (1H, d, J = 11.3 Hz), 1.81 (3H, d, J = 5.1 Hz),1.78-1.87 (1H, m), 1.23 (4H, d, J = 6.6 Hz), 1.01 (5H, t, J = 5.7 Hz)358.2 187

1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (1H, d, J = 6.6 Hz), 7.30 (1 H, d,J = 7.3 Hz), 7.22 (1H, t, J = 8.1 Hz), 7.14 (1H, t, J = 7.3 Hz), 3.87(3H, t, J = 7.1 Hz), 3.30 (1H, br. s.), 2.59 (2 H, br. s.), 2.45 (1H,br. s.), 1.66 (2H, d, J = 5.9 Hz), 1.69 (1H, br. s.), 1.29 (5 H, d, J =2.6 Hz), 1.22 (5H, d, J = 6.2 Hz), 0.99 (6H, br. s.), 0.84 (3H, t, J =6.8 Hz) 360.3 188

1H NMR (400 MHz, DMSO-d6) δ ppm 9.32 (1H, d, J = 8.1 Hz), 8.15 (1 H, d,J = 7.7 Hz), 7.32 (1H, br. s.), 7.25 (2H, d, J = 7.7 Hz), 7.18 (1H, br.s.), 7.20 (1H, d, J = 7.0 Hz), 5.35 (1H, d, J = 4.4 Hz), 5.30 (1H, d, J= 4.8 Hz), 4.54 (1H, d, J = 4.4 Hz), 3.71 (3H, d, J = 7.0 Hz), 3.13 (1H,dd, J = 16.3, 4.6 Hz), 2.85 (1H, d, J = 16.5 Hz), 1.82 (1 H, dd, J =4.2, 2.7 Hz), 162 (6H, d, J = 15.0 Hz), 1.14 (4H, d, J = 7.3 Hz), 1.03(2H, t, J = 11.0 Hz) 405.2 189

1H NMR (400 MHz, DMSO-d6) δ ppm 1.77-1.87 (m, 4H) 1.97 (d, J = 6.59 Hz,2H) 2.73-2.80 (m, 1H) 2.85 (d, J = 16.11 Hz, 1H) 3.14 (dd, J = 16.47,4.39 Hz, 1H) 3.92 (d, J = 7.32 Hz, 3H) 4.55 (br. s., 1H) 5.28-5.38 (m,2H) 7.18-729 (m, 5H) 7.35 (d, J = 7.32 Hz, 1H) 8.15 (d, J = 7.69 Hz, 1H) 9.32 (d, J = 8.05 Hz, 1H) 377.2 190

1H NMR (400 MHz, DMSO-d6) δ ppm 9.31 (1H, d, J = 8.1 Hz), 8.15 (1 H, d,J = 7.7 Hz), 7.18-7.29 (5H, m), 5.32 (1H, dd, J = 15.7, 4.8 Hz), 4.54 (1H, d, J = 2.2 Hz), 3.87 (2H, t, J = 7.0 Hz), 3.13 (1H, dd, J = 16.7, 4.6Hz), 2.85 (1H, d, J = 16.1 Hz), 1.66 (1H, br. s.), 1.69 (2H, d, J = 7.0Hz), 1.30 (5H, d, J = 3.3 Hz), 1.23 (1H, br. s.), 0.84 (3 H, t, J = 6.8Hz) 379.2 191

1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H, d, J = 7.3 Hz), 8.06 (1 H, d,J = 7.7 Hz), 7.31 (1H, d, J = 7.7 Hz), 7.22 (1H, t, J = 7.5 Hz), 7.14(1H, t, J = 7.7 Hz), 4.83 (1H, d, J = 4.8 Hz), 3.72 (2H, d, J = 7.0 Hz),3.52 1H, br. s.), 3.30-3.39 (1H, m), 2.04 (1H, d, J = 2.9 Hz), 1.84 (2H,d, J = 18.3 Hz), 1.83 (7H, d, J = 15.7 Hz), 1.28 (4H, d, J = 7.0 Hz),1.15 (3H, d, J = 7.7 Hz), 1.03 (2H, d, J = 10.2 Hz), 1.07 (1H, br. s.)371.2 192

1H NMR (400 MHz, DMSO-d6) δ ppm 7.33 (1H, d, J = 7.7 Hz), 7.22 (1 H, t,J = 7.9 Hz), 7.14 (1H, t, J = 7.3 Hz), 4.83 (1H, d, J = 5.1 Hz), 3.92(2H, d, J = 7.3 Hz), 3.48-3.56 (1H, m), 3.35 (1H, d, J = 4.4 Hz), 3.34(1H, d, J = 17.2 Hz), 2.74-2.81 (1H, m), 1.94- 2.05 (3H, m), 1.82 (3H,d, J = 5.1 Hz), 1.78-1.89 (2H, m), 1.66 (1H, br. s.), 1.60 (1H, br. s.),1.28 (5H, d, J = 6.6 Hz), 1.21 (1H, br. s.) 343.2 193

1H NMR (400 MHz, DMSO-d6) δ ppm 8.74 (1H, d, J = 7.3 Hz), 8.06 (1 H, d,J = 7.7 Hz), 7.29-7.33 (1H, m), 7.22 (1H, t, J = 7.3 Hz), 7.15 (1H, t, J= 7.7 Hz), 4.82 (1H, d, J = 5.1 Hz), 3.87 (2H, t, J = 7.1 Hz), 3.49-3.56(1 H, m), 3.35 (1H, d, J = 4.0 Hz), 3.25 (1 H, br. s.), 2.04 (1H, br.s.), 1.87 (1H, d, J = 8.4 Hz), 1.67 (2H, d, J = 7.0 Hz), 1.70 (1H, br.s.), 1.60 (1H, br. s.), 1.23-1.33 (9H, m), 0.85 (3H, t, J = 6.6 Hz)345.2 194

1H NMR (400 MHz, DMSO-d6) δ ppm 8.62 (1H, d, J = 7.3 Hz), 8.04 (1 H, d,J = 7.7 Hz), 7.30 (1H, d, J = 8.1 Hz), 7.21 (1H, t, J = 7.5 Hz), 7.14(1H, t, J = 7.7 Hz), 4.54 (1H, d, J = 3.7 Hz), 3.71 (2H, br. s.),3.62-3.68 (1H, m), 3.43-3.51 (1H, m), 3.26 (0H, br. s.), 1.92-1.99 (2H,m), 1.76-1.86 (3H, m), 1.57-1.69 (5H, m), 1.32 (3H, d, J = 11.0 Hz),1.24-1.39 (2H, m), 1.10- 1.19 (3H, m), 0.97-1.08 (2H, m) 371.2 195

1H NMR (400 MHz, DMSO-d6) δ ppm 8.62 (1H, d, J = 7.7 Hz), 7.32 (1 H, d,J = 7.7 Hz), 7.22 (1H, t, J = 7.7 Hz), 7.14 (1H, J = 7.3 Hz), 4.54 (1H,3.60-3.69 (1H, m), 3.47 (1H, dd, (1H, t, J = 7.5 Hz), 1.97 (3H, d, J =4.0 Hz), 1.94 (2H, br. s.), 1.83 (3H, d, J = 7.0 Hz), 1.81 (2H, br. s.),1.76 (1H, br. s.), 1.32 (3H, d, J = 13.2 Hz), 1.27- 1.37 (1H, m) 343.2196

1H NMR (400 MHz, DMSO-d6) δ ppm 8.62 (1H, d, J = 7.3 Hz), 8.04 (1 H, d,J = 7.7 Hz), 7.30 (1H, d, J = 7.7 Hz), 7.22 (1H, t, J = 7.7 Hz), 7.14(1H, t, J = 7.7 Hz), 4.55 (1H, d, J = 4.0 Hz), 3.86 (2H, t, J = 7.1 Hz),3.60-3.70 (1 H, m), 3.43-3.52 (1H, m), 1.89-2.00 (2H, m), 1.83 (2H, d, J= 10.2 Hz), 1.60-1.75 (1H, m), 1.68 (2H, d, J = 7.0 Hz), 1.29 (5H, d, J= 9.9 Hz), 1.21-1.40 (4H, m), 0.84 (2H, t, J = 6.8 Hz) 345.2 197

1H NMR (400 MHz, DMSO-d6) δ ppm 9.00 (1H, d, J = 8.1 Hz), 8.10 (1 H, d,J = 8.1 Hz), 7.31 (1H, d, J = 8.1 Hz), 7.34 (1H, d, J = 7.3 Hz), 7.13-7.23 (3H, m), 5.09 (1H, d, J = 6.6 Hz), 3.68 (2H, d, J = 7.0 Hz), 3.27(1H, s), 2.70-2.87 (2H, m), 2.08 (1H, d, J = 5.9 Hz), 1.91 (1H, dd, J =12.1, 5.9 Hz), 1.81 (1H, br. s.), 1.63 (2H, d, J = 5.5 Hz), 1.60 (6H, d,J = 13.9 Hz), 1.12 (4H, d, J = 7.7 Hz), 1.03 (1H, br. s.), 0.99 (1H, d,J = 9.2 Hz) 403.2 198

1H NMR (400 MHz, DMSO-d6) δ ppm 9.00 (1H, d, J = 7.7 Hz), 8.10 (1 H, d,J = 7.7 Hz), 7.34 (2H, d, J = 7.3 Hz), 7.14-7.26 (4H, m), 5.06-5.14 (1H,m), 3.89 (2H, d, J = 7.0 Hz), 2.82 (0H, br. s.), 2.70-2.79 (3H, m),2.00- 2.11 (1H, m), 1.87-1.98 (1H, m), 1.94 (2H, d, J = 2.9 Hz),1.76-1.86 (1 H, m), 1.82 (5H, dd, J = 12.3, 5.7 Hz), 1.74 (1H, br. s.)376.2 (M + H) 199

1H NMR (400 MHz, DMSO-d6) δ ppm 9.00 (1H, d, J = 8.1 Hz), 8.11 (1 H, d,J = 8.1 Hz), 7.32 (1H, d, J = 8.8 Hz), 7.25 (1H, t, J = 7.5 Hz), 7.17(2H, d, J = 10.6 Hz), 3.84 (2H, t, J = 7.1 Hz), 2.72-2.87 (2H, m), 2.05(1H, d, J = 5.9 Hz), 2.02-2.11 (1H, m), 1.91 (1 H, dd, J = 12.3, 6.0Hz), 1.84 (2H, d, J = 5.5 Hz), 1.81 (1H, br. s.), 1.64 (1H, br. s.),1.66 (2H, d, J = 7.0 Hz), 1.28 (4 H, d, J = 3.3 Hz), 1.23 (1H, br. s.),0.83 (2H, t, J = 6.6 Hz) 377.2 200

1H NMR (400 MHz, DMSO-d6) δ ppm 9.19 (1H, d, J = 8.8 Hz), 8.04 (1 H, d,J = 7.7 Hz), 7.62 (1H, br. s.), 7.32 (1H, d, J = 7.7 Hz), 7.23 (1H, t, J= 7.3 Hz), 7.11-7.19 (2H, m), 4.25 (1H, d, J = 8.8 Hz), 3.73 (1H, d, J =3.7 Hz), 3.74 (1H, br. s.), 1.83 (1H, br. s.), 1.63 (5H, d, J = 15.4Hz), 1.15 (4H, d, J = 7.3 Hz), 1.00 (11H, s) 386.2 201

1H NMR (400 MHz, DMSO-d6) δ ppm 9.19 (1H, d, J = 8.8 Hz), 8.03 (1 H, d,J = 8.1 Hz), 7.62 (1H, br. s.), 7.33 (1H, d, J = 7.7 Hz), 7.22 (1H, t, J= 7.5 Hz), 7.11-7.18 (2H, m), 4.24 (1H, d, J = 8.8 Hz), 3.93 (2H, dd, J= 6.8, 2.7 Hz), 1.98 (2H, d, J = 6.6 Hz), 1.77- 1.89 (4H, m), 1.00 (10H,s) 358.2 202

1H NMR (400 MHz, DMSO-d6) δ ppm 9.19 (1H, d, J = 8.8 Hz), 8.04 (1 H, d,J = 8.1 Hz), 7.62 (1H, br. s.), 7.31 (1H, d, J = 7.7 Hz), 7.23-7.27 (1H,m), 7.12-7.23 (2H, m), 4.25 (1H, d, J = 8.8 Hz), 3.89 (2H, t, J = 6.6Hz), 3.22 (0H, br. s.), 1.64-1.74 (1H, m), 1.64-1.74 (1H, m), 1.16-1.37(4H, m), 1.00 (10 H, s), 0.85 (3 H, t, J = 6.4 Hz) 360.2 203

1H NMR (400 MHz, DMSO-d6) δ ppm 9.08 (1H, d, J = 8.1 Hz), 8.04 (1 H, d,J = 7.7 Hz), 7.61 (1H, br. s.), 7.32 (1H, d, J = 8.1 Hz), 7.23 (1H, t, J= 7.3 Hz), 7.12-7.18 (1H, m), 4.29 (1H, dd, J = 8.2, 4.9 Hz), 3.73 (2H,d, J = 5.5 Hz), 2.15 (1H, dd, J = 12.3, 6.8 Hz), 1.83 (1H, br. s.), 1.64(5H, d, J = 16.5 Hz), 1.10-1.20 (3H, m), 1.01-1.10 (2H, m), 0.88-0.98(6H, m) 372.2 204

1H NMR (400 MHz, DMSO-d6) δ ppm 9.08 (1H, d, J = 8.4 Hz), 8.03 (1 H, d,J = 7.7 Hz), 7.61 (1H, br. s.), 7.34 (1H, d, J = 7.7 Hz), 7.23 (1H, t, J= 7.5 Hz), 7.15 (2H, d, J = 6.6 Hz), 4.29 (1H, dd, J = 8.2, 4.9 Hz),3.94 (2H, d, J = 7.0 Hz), 2.78 (1H, ddd, J = 14.7, 7.2, 7.0 Hz), 2.15(1H, dd, J = 11.9, 6.4 Hz), 1.98 (2H, d, J = 5.5 Hz), 1.79-1.89 (4 H,m), 0.88-0.98 (7H, m) 344.2 205

1H NMR (400 MHz, DMSO-d6) δ ppm 9.08 (1H, d, J = 8.4 Hz), 8.03 (1 H, d,J = 8.1 Hz), 7.61 (1H, br. s.), 7.31 (1H, d, J = 7.7 Hz), 7.23 (1H, t, J= 7.5 Hz), 7.12-7.18 (2 m), 4.29 (1H, dd, J = 8.2, 4.9 Hz), 3.88 (2H, t,J = 7.0 Hz), 2.10-2.20 (1H, m), 1.68 (0H, br. s.), 1.61-1.77 (2H, m),1.22-1.41 (4 H, m), 0.86 (2H, t, J = 6.6 Hz), 0.81- 1.00 (7H, m) 346.2206

1H NMR (400 MHz, DMSO-d6) δ ppm 9.40 (1H, s), 8.04 (1H, d, J = 7.7 Hz),7.44 (1H, br. s.), 7.26-7.33 (1H, m), 7.21 (1H, t, J = 7.9 Hz), 7.13(1H, t, J = 7.9 Hz), 7.07 (1H, br. s.), 3.71 (2 H, d, J = 7.3 Hz), 1.81(1H, br. s.), 1.64 (5H, d, J = 15.7 Hz), 1.55 (6H, s), 1.15 (2H, d, J =7.3 Hz), 1.04 (2H, q, J = 10.9 Hz) 358.2 207

1H NMR (400 MHz, DMSO-d6) δ ppm 9.40 (1H, s), 8.04 (1H, d, J = 8.1 Hz),7.45 (1H, br. s.), 7.31 (1H, d, J = 7.7 Hz), 7.21 (1H, t, J = 7.7 Hz),7.13 (1H, t, J = 7.7 Hz), 7.09 (1H, br. s.), 3.92 (2H, d, J = 7.0 Hz),1.98 (2H, d, J = 5.5 Hz), 1.78-1.88 (4H, m), 1.55 (7H, s) 330.2 208

1H NMR (400 MHz, DMSO-d6) δ ppm 9.40 (1H, s), 8.04 (1H, d, J = 8.1 Hz),7.45 (1H, br. s.), 7.30 (1H, d, J = 7.7 Hz), 7.22 (1H, t, J = 7.5 Hz),7.13 (1H, t, J = 7.7 Hz), 7.08 (1H, br. s.), 3.87 (2H, t, J = 7.0 Hz),1.67 (1H, br. s.), 1.69 (2H, d, J = 6.6 Hz), 1.55 (7 H, s), 1.23-1.40(4H, m), 0.81-0.91 (2H, m) 332.2 209

1H NMR (400 MHz, DMSO-d6) δ ppm 9.01 (1H, s), 8.02 (1H, d, J = 7.7 Hz),7.37 (1H, br. s.), 7.31 (1H, s), 7.20-7.26 (1H, m), 7.14 (1H, t, J = 7.7Hz), 6.83 (1H, br. s.), 3.74 (2H, d, J = 7.3 Hz), 2.05 (2H, d, J = 13.2Hz), 1.84 (1H, br. s.), 1.76 (3H, t, J = 13.5 Hz), 1.68 (4H, br. s.),1.60 (4H, br. s.), 1.40 (2H, d, J = 13.2 Hz), 1.32- 1.48 (1H, m), 1.24(1H, d, J = 3.7 Hz), 1.16 (3H, d, J = 7.0 Hz), 1.09 (1H, br. s.), 1.05(2H, d, J = 12.1 Hz) 398.2 210

1H NMR (400 MHz, DMSO-d6) δ ppm 9.01 (1H, s), 8.01 (1H, d, J = 8.1 Hz),7.37 (1H, br. s.), 7.34 (1H, d, J = 7.7 Hz), 7.23 (1H, t, J = 7.5 Hz),7.14 (1H, t, J = 7.7 Hz), 6.83 (1H, br. s.), 3.95 (2H, d, J = 7.0 Hz),1.95-2.09 (4H, m), 1.76 (2H, t, J = 13.5 Hz), 1.85 (4H, d, J = 2.9 Hz),1.61 (3H, d, J = 10.2 Hz), 1.40 (2H, q, J = 12.4 Hz), 1.18-1.30 (1H, m)370.2 211

1H NMR (400 MHz, DMSO-d6) δ ppm 9.01 (1H, s), 8.02 (1H, d, J = 8.1 Hz),7.32 (1H, d, J = 7.7 Hz), 7.36 (1H, br. s.), 7.23 (1H, t, J = 7.7 Hz),7.14 (1 H, t, J = 7.7 Hz), 6.83 (1H, br. s.), 3.90 (2H, t, J = 7.1 Hz),2.05 (2H, d, J = 13.5 Hz), 1.65-1.80 (4H, m), 1.61 (3H, d, J = 11.0 Hz),1.33 (4H, d, J = 6.6 Hz), 128-1.48 (2H, m), 1.23 (2H, d, J = 10.2 Hz),0.82-0.91 (2H, m) 372.2 212

1H NMR (400 MHz, DMSO-d6) δ ppm 9.72 (1H, d, J = 7.0 Hz), 7.97 (1 H, d,J = 8.1 Hz), 7.83 (1H, br. s.), 7.48 (2H, d, J = 7.3 Hz), 7.33 (3H, dd,J = 17.6, 9.9 Hz), 7.29-7.40 (2H, m), 7.22 (1H, t, J = 7.5 Hz), 7.12(1H, t, J = 7.9 Hz), 5.46 (1H, d, J = 7.0 Hz), 3.94 (2H, d, J = 7.0 Hz),2.77 (1H, d, J = 7.3 Hz), 1.99 (2H, d, J = 7.7 Hz), 1.86 (1H, br. s.),1.79-1.85 (1H, m), 1.83 (2H, d, J = 4.0 Hz) 378.2 213

1H NMR (400 MHz, DMSO-d6) δ ppm 9.73 (1H, d, J = 7.0 Hz), 7.98 (1 H, d,J = 7.7 Hz), 7.84 (1H, br. s.), 7.48 (2H, d, J = 7.3 Hz), 7.38 (2H, t, J= 7.3 Hz), 7.31 (3H, d, J = 2.9 Hz), 7.22 (1H, t, J = 7.5 Hz), 7.12 (1H,t, J = 7.7 Hz), 5.46 (1H, d, J = 7.0 Hz), 3.89 (2H, t, J = 7.1 Hz), 1.68(0H, br. s.), 1.65 1.74 (3H, m), 1.32 (4H, d, J = 3.3 Hz), 0.86 (3H, t,J = 6.8 Hz) 380.2 214

1H NMR (400 MHz, DMSO-d6) δ ppm 9.03 (1H, d, J = 7.7 Hz), 7.98 (1 H, d,J = 7.7 Hz), 7.67 (1H, br. s.), 7.29 (1H, d, J = 8.1 Hz), 7.19-7.26 (6H,m), 7.12 (1H, t, J = 7.7 Hz), 4.59-4.66 (1H, m), 3.70 (2H, d, J = 7.0Hz), 3.16 (1H, dd, J = 13.5, 4.8 Hz), 2.97 (1H, dd, J = 13.5, 7.7 Hz),1.79 (1H, br. s.), 1.61 (5H, br. s.), 1.11-1.20 (3H, m), 1.03 (2H, t, J= 11.2 Hz) 420.0 215

1H NMR (400, MHz, DMSO-d6) δ ppm 9.03 (1H, d, J = 7.7 Hz), 7.97 (1 H, d,J = 8.1 Hz), 7.67 (1H, br. s.), 7.31 (1H, d, J = 7.7 Hz), 7.18-7.27 (6H,m), 7.12 (1H, t, J = 7.7 Hz), 4.58-4.67 (1H, m), 3.91 (2H, d, J = 7.3Hz), 3.16 (1H, dd, J = 13.9, 5.1 Hz), 2.97 (1H, dd, J = 13.9, 8.1 Hz),2.71-2.81 (1H, m), 1.92-2.01 (2H, m), 1.76-1.87 (4 H, m) 392.2 216

1H NMR (400 MHz, DMSO-d6) δ ppm 9.03 (1H, d, J = 7.7 Hz), 7.98 (1 H, d,J = 8.1 Hz), 7.66 (1H, br. s.), 7.19- 7.30 (8H, m), 7.13 (1H, t, J = 7.9Hz), 4.63 (1H, d, J = 5.5 Hz), 3.86 (2H, t, J = 7.1 Hz), 3.16 (1H, dd, J= 13.9, 5.1 Hz), 2.98 (1H, dd, J = 13.9, 8.1 Hz), 1.67 (2H, qd, J = 7.0,6.8 Hz), 1.31 (3 H, d, J = 6.2 Hz), 1.25-1.35 (1H, m), 0.86 (3H, t, J =6.8 Hz) 394.2 217

1H NMR (400 MHz, DMSO-d6) δ ppm 9.19 (1H, d, J = 9.1 Hz), 8.04 (1 H, d,J = 8.1 Hz), 7.61 (1H, br. s.), 7.27- 7.31 (1H, m), 7.24 (1H, t, J = 7.7Hz), 7.14 (2H, d, J = 7.7 Hz), 4.26 (1H, d, J = 9.1 Hz), 3.82 (2H, t, J= 6.6 Hz), 2.29 (1H, qd, J = 7.7, 7.5 Hz), 1.99 (1 H, d, J = 3.7 Hz),1.96-2.03 (1H, m), 1.81 (2H, d, J = 7.3 Hz), 1.79-1.85 (1 H, m),1.75-1.79 (1H, m), 1.62 (2H, q, J = 8.4 Hz), 1.00 (9H, s) 372.2 218

1H NMR (400 MHz, DMSO-d6) δ 9.19 (1H, d, J = 8.1 Hz), 8.04 (1 H, d, J =7.7 Hz), 7.61 (1H, br. s.), 7.29- 7.33 (1H, m), 7.24 (1H, t, J = 7.7Hz), 7.14 (2H, d, J = 8.1 Hz), 4.25 (1H, d, J = 8.8 Hz), 3.91 (1H, d, J= 3.7 Hz), 3.91 (1H, d, J = 17.2 Hz), 1.75-1.83 (2 H, m, J = 7.2, 7.2,7.2, 7.2 Hz), 1.25 (2 H, q, J = 7.1 Hz), 1.00 (9H, s), 0.74 (1 H, m),0.39 (2H, d, J = 7.7 Hz), 0.02 (2H, d, J = 4.4 Hz) 372.2 219

1H NMR (400 MHz, DMSO-d6) δ ppm 9.17 (1H, d, J = 8.8 Hz), 7.79 (1 H, t,J = 7.3 Hz), 7.63 (1H, br. s.), 7.41 (1H, d, J = 8.1 Hz), 7.15 (4H, br.s.), 5.24 (2H, br. s.), 4.27 (1H, d, J = 8.8 Hz), 1.00 (11H, s) 381.2220

1H NMR (400 MHz, DMSO-d6) δ ppm 9.13 (1H, d, J = 8.8 Hz), 8.76 (1 H, d,J = 4.8 Hz), 8.07 (1H, d, J = 5.5 Hz), 7.64 (1H, br. s.), 7.43 (1H, t, J= 4.6 Hz), 7.16 (3H, br. s.), 6.90- 7.00 (1H, m), 5.36 (2H, s), 4.27(1H, d, J = 8.8 Hz), 0.99 (9H, s), 0.93 (3H, s) 382.2 221

1H NMR (400 MHz, DMSO-d6) δ ppm 9.11 (1H, d, J = 8.8 Hz), 8.05 (1 H, d,J = 8.1 Hz), 7.63 (1H, br. s.), 7.09- 7.26 (3H, m), 5.17 (2H, s), 4.26(1 H, d, J = 9.5 Hz), 2.31-2.40 (4H, m), 2.25 (2H, s), 1.01 (9H, s)385.2 222

1H NMR (400 MHz, DMSO-d6) δ ppm 9.16 (1H, d, J = 8.8 Hz), 8.05 (1 H, d,J = 7.7 Hz), 7.61 (1H, br. s.), 7.33 (1H, d, J = 8.1 Hz), 7.24 (1H, t, J= 7.5 Hz), 7.12-7.19 (1H, m), 4.26 (1H, d, J = 8.8 Hz), 3.98 (2H, t, J =6.6 Hz), 2.60 (2H, t, J = 7.1 Hz), 2.01 (2H, t, J = 7.0 Hz), 1.00 (9H,s), 0.93 (2H, s) 357.2 223

1H NMR (400 MHz, DMSO-d6) δ ppm 9.18 (1H, d, J = 8.8 Hz), 8.04 (1 H, d,J = 7.7 Hz), 7.61 (1H, br. s.), 7.35 (1H, d, J = 7.7 Hz), 7.24 (1H, t, j= 7.3 Hz), 7.11-7.19 (2H, m), 4.25 (1H, d, J = 8.8 Hz), 3.94 (2H, t, J =6.6 Hz), 2.55-2.58 (1H, m), 1.78 (0H, d, J = 7.7 Hz), 1.71-1.84 (2H, m),1.64 (0H, d, J = 7.7 Hz), 1.55-1.68 (2H, m), 1.00 (9H, s), 0.93 (2H, s)371.2 224

1H NMR (400 MHz, DMSO-d6) δ ppm 9.18 (1H, d, J = 8.8 Hz), 7.62 (1 H, br.s.), 7.31 (1H, d, J = 5.5 Hz), 7.21 (1H, t, J = 7.5 Hz), 7.09-7.18 (2H,m), 4.25 (1H, d, J = 8.8 Hz), 3.85-3.97 (2 H, m), 3.77-3.85 (0H, m),3.77-3.85 (2H, m), 3.63-3.74 (1H, m), 3.22 (0 H, br. s.), 1.73-1.83 (1H,m), 1.65 (1 H, d, J = 12.1 Hz), 1.38-1.54 (3H, m), 1.15-1.35 (1H, m),1.00 (8H, s), 0.93 (2H, s) 389.2 (M + H) 225

1H NMR (400 MHz, DMSO-d6) δ ppm 10.50 (1H, br. s.), 8.34 (1H, s), 8.14(1H, d, J = 5.1 Hz), 7.91 (1H, d, J = 2.6 Hz), 7.01 (1H, d, J = 5.1 Hz),3.69 (1H, s), 3.66 (2H, d, J = 7.3 Hz), 1.81 (1H, dd, J = 10.2, 4.4 Hz),1.66 (2 H, d, J = 4.8 Hz), 1.59 (3H, d, J = 11.0 Hz), 1.15 (3H, t, J =7.7 Hz), 1.00 (4H, s), 0.93 (9H, s) 388.3 (M + H) 226

1H NMR (400 MHz, DMSO-d6) δ ppm 8.99 (1H, d, J = 9.1 Hz), 8.19 (1 H, d,J = 8.1 Hz), 8.15 (1H, d, J = 4.0 Hz), 7.63 (1H, br. s.), 7.16 (1H, br.s.), 7.18 (1H, d, J = 7.7 Hz), 4.25 (1H, d, J = 8.8 Hz), 3.75 (2H, d, J= 7.0 Hz), 1.87-1.97 (1H, m), 1.59-1.70 (5H, m), 1.12-1.21 (3H, m), 1.00(11H, s) 387.2 227

1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 (s, 9H) 2.81 (td, J = 10.98, 4.03Hz, 2H) 4.17 (t, J = 6.77 Hz, 2H) 4.27 (d, J = 9.15 Hz, 1H) 7.19 (d, J =7.69 Hz, 1H) 7.14 (br. s., 1H) 7.26 (t, J = 7.50 Hz, 1H) 7.36 (d, J =7.69 Hz, 1H) 7.62 (br. s., 1H) 8.05 (d, J = 7.69 Hz, 1H) 9.12 (d, J =8.78 Hz, 1H) 386.1 Example Structure Number Chemical Name 228

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Example Structure Mass Number Compound Name NMR Data (M) 266

1H NMR (400 MHz, DMSO-d6) δ ppm 1.05 (d, J = 10.62 Hz, 2H) 1.17 (d, J =6.96 Hz, 3H) 1.24 (br. s., 1H) 1.33- 1.44 (m, 1H) 1.39 (d, J = 10.25 Hz,1H) 1.61 (d, J = 9.88 Hz, 4H) 1.67 (br. s., 3H) 1.83 (br. s., 1H) 1.77(d, J = 16.11 Hz, 3 H) 2.04 (d, J = 13.18 Hz, 2H) 2.37 (s, 3 H) 3.30(br. s., 1H) 3.71 (d, J = 7.32 Hz, 2 H) 6.82 (br. s., 1H) 6.95 (d, J =7.69 Hz, 1 H) 7.15 (s, 1H) 7.36 (br. s., 1H) 7.87 (d, J = 8.05 Hz, 1H)8.98 (s, 1H) 412.2 267

1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (d, J = 4.39 Hz, 6H) 1.07 (br. s.,1H) 1.03 (d, J = 9.88 Hz, 2H) 1.16 (d, J = 6.22 Hz, 3H) 1.24 (d, J =15.37 Hz, 1H) 1.57- 1.69 (m, 7H) 1.82 (d, J = 19.03 Hz, 1H) 1.81 (d, J =4.76 Hz, 1H) 2.37 (s, 3H) 3.69 (d, J = 6.95 Hz, 2H) 4.37 (d, J = 5.12Hz, 1H) 6.95 (d, J = 8.05 Hz, 1H) 7.12 (d, J = 16.47 Hz, 2H) 7.64 (br.s., 1H) 7.89 (d, J = 8.42 Hz, 1H) 8.96 (d, J = 8.05 Hz, 1H) 400.2 268

1H NMR (400 MHz, DMSO-d6) δ ppm 0.97-1.08 (m, 1H) 0.97-1.08 (m, 1H)1.12-1.20 (m, 3H) 1.58-1.64 (m, 3H) 1.64-1.69 (m, 2H) 1.81 (br. s., 1H)2.36 (s, 3H) 2.96 (dd, J = 13.73, 7.87 Hz, 1H) 3.15 (dd, J = 13.91, 5.12Hz, 1H) 3.67 (d, J = 7.32 Hz, 2H) 4.58-4.64 (m, 1H) 6.93 (d, J = 8.42Hz, 1H) 7.12 (s, 1 H) 7.17-7.27 (m, 5H) 7.67 (br. s., 1H) 7.83 (d, J =8.42 Hz, 1H) 9.00 (d, J = 7.69 Hz, 1H) 434.2 269

1H NMR (400 MHz, DMSO-d6) δ ppm 0.88-0.97 (m, 6H) 1.04 (d, J = 9.52 Hz,2H) 1.08 (br. s., 1H) 1.16 (d, J = 6.95 Hz, 3H) 1.64 (d, J = 16.84 Hz,5H) 1.83 (br. s., 1H) 2.14 (dd, J = 12.45, 6.22 Hz, 1H) 2.37 (s, 3H)3.23 (br. s., 1H) 3.69 (br. s., 1H) 3.71 (d, J = 1.83 Hz, 1H) 4.28 (dd,J = 8.42, 5.12 Hz, 1H) 6.95 (d, J = 8.05 Hz, 1H) 7.15 (s, 2H) 7.60 (br.s., 1H) 7.89 (d, J = 8.05 Hz, 1H) 9.05 (d, J = 8.42 Hz, 1H) 386.2 270

1H NMR (400 MHz, DMSO-d6) δ ppm 8.95 (1H, d, J = 8.1 Hz), 7.88 (1H, d, J= 8.1 Hz), 7.84 (1H, br. s.), 7.12 (2H, d, J = 16.8 Hz), 6.96 (1H, d, J= 8.1 Hz), 4.37 (1H, d, J = 5.5 Hz), 3.68 (2H, d, J = 7.0 Hz), 2.36 (3H,s), 1.81 (1H, dd, J = 13.2, 6.2 Hz), 1.57-1.68 (8H, m), 1.15 (3H, d, J =6.6 Hz), 1.07 (1H, br. s.), 0.93 (4H, d, J = 1.8 Hz), 0.92-1.04 (1H, m),0.92 (3H, br. s.) 400.2 271

1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (1H, d, J = 9.2 Hz), 7.61 (1H, br.s.), 7.23 (1H, d, J = 3.7 Hz), 7.16 (2H, d, J = 7.3 Hz), 6.98 (1H, dd, J= 11.0, 8.8 Hz), 4.22 (1H, d, J = 9.2 Hz), 3.72 (2H, d, J = 7.0 Hz),1.76-1.86 (1H, m), 1.63 (5H, d, J = 17.2 Hz), 1.16 (3H, t, J = 7.1 Hz),1.00 (11H, s) 404.2 272

1H NMR (400 MHz, DMSO-d6) δ ppm 9.10 (1H, d, J = 8.8 Hz), 8.16 (1H, d, J= 8.4 Hz), 7.98 (1H, s), 7.59-7.65 (2 H, m), 7.16 (1H, br. s.), 4.26(1H, d, J = 8.8 Hz), 3.81 (3H, d, J = 7.3 Hz), 3.85 (1H, br. s.),3.21-3.24 (1H, m), 2.09 (1 H, br. s.), 1.55 (2H, d, J = 11.3 Hz), 1.31(0H, d, J = 3.7 Hz), 1.27-1.38 (2H, m), 1.00 (11H, s) 413.2 273

1H NMR (400 MHz, DMSO-d6) δ ppm 0.98-1.21 (m, 9H) 1.54-1.75 (m, 4H)1.54-1.75 (m, 8H) 1.80 (br. s., 0H) 2.35 (s, 3H) 2.48 (br. s., 2H) 3.67(dd, J = 7.32, 3.66 Hz, 2H) 4.20-4.30 (m, 1 H) 6.93 (d, J = 8.78 Hz, 1H)7.12 (br. s., 2 H) 7.57 (br. s., 1H) 7.86 (d, J = 8.05 Hz, 1 H) 9.02 (d,J = 8.78 Hz, 1H) 426.2 274

1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (d, J = 6.22 Hz, 3H) 1.35 (br. s.,2H) 1.55 (br. s., 2H) 2.02-2.13 (m, 1H) 3.18-3.27 (m, 2H) 3.79 (d, J =6.95 Hz, 3H) 3.85 (br. s., 2H) 4.11-4.22 (m, 1 H) 4.14 (dd, J = 7.69,2.93 Hz, 1H) 7.14 (d, J = 7.69 Hz, 2H) 7.23 (t, J = 7.50 Hz, 1 H) 7.36(d, J = 8.05 Hz, 1H) 7.44 (br. s., 1 H) 8.04 (d, J = 8.05 Hz, 1H) 9.19(d, J = 7.69 Hz, 1H) 376.2 275

1H NMR (400 MHz, DMSO-d6) δ ppm 9.07 (1H, d, J = 8.4 Hz), 8.04 (1H, d, J= 8.1 Hz), 7.61 (1H, br. s.), 7.37 (1H, d, J = 7.3 Hz), 7.24 (1H, t, J =7.7 Hz), 7.12- 7.19 (2H, m), 6.97 (1H, s), 4.29 (1H, dd, J = 8.4, 4.8Hz), 3.79 (2H, d, J = 7.0 Hz), 3.83 (2H, d, J = 7.7 Hz), 3.67 (1H, d, J= 7.3 Hz), 3.19-3.25 (2H, m), 2.12- 2.17 (1H, m), 1.49-1.56 (2H, m),1.32 (0H, d, J = 8.4 Hz), 1.26-1.37 (2H, m), 0.89-0.98 (6H, m), 0.81(1H, d, J = 6.6 Hz) 374.2 276

1H NMR (400 MHz, DMSO-d6) δ ppm 9.00 (1H, d, J = 8.1 Hz), 8.11 (1H, d, J= 8.1 Hz), 7.36 (2H, t, J = 8.1 Hz), 7.15- 7.25 (4H, m), 5.10 (1H, d, J= 6.2 Hz), 3.82 (1H, d, J = 2.9 Hz), 3.79 (1H, d, J = 2.2 Hz), 3.74 (2H,d, J = 7.3 Hz), 3.21 (2H, t, J = 11.5 Hz), 2.82 (1H, t, J = 5.1 Hz),2.77 (1H, t, J = 5.5 Hz), 2.05 (1H, d, J = 6.6 Hz), 2.00-2.10 (1H, m),1.91 (1 H, d, J = 6.2 Hz), 1.82 (1H, br. s.), 1.84 (2 H, d, J = 5.5 Hz),1.50 (2H, d, J = 13.2 Hz), 1.28 (1H, dd, J = 12.3, 4.2 Hz), 1.23- 1.34(1H, m) 406.2 (M + H) 277

1H NMR (400 MHz, DMSO-d6) δ ppm 9.72 (1H, d, J = 6.6 Hz), 7.98 (1H, d, J= 8.1 Hz), 7.84 (1H, br. s.), 7.48 (2H, d, J = 7.3 Hz), 7.36 (4H, dt, J= 12.5, 7.6 Hz), 7.13 (1H, t, J = 7.9 Hz), 5.45 (1H, d, 7.31 (1H, br.s.), 7.22 (1H, t, J = 7.5 Hz), J = 7.0 Hz), 3.79 (3H, d, J = 7.0 Hz),3.84 (1H, d, J = 11.3 Hz), 3.24 (2H, t, J = 11.0 Hz), 2.02-2.13 (1H, m),1.54 (2H, d, J = 11.7 Hz), 1.32 (1H, d, J = 12.1 Hz), 1.33 (1H, q, J =12.2 Hz) 408.2 278

1H NMR (400 MHz, DMSO-d6) δ ppm 9.02 (1H, d, J = 7.7 Hz), 7.98 (1H, d, J= 8.1 Hz), 7.67 (1H, br. s.), 7.35 (1H, d, J = 7.7 Hz), 7.19-7.28 (7H,m), 7.13 (2 H, t, J = 7.7 Hz), 4.62 (1H, d, J = 5.1 Hz), 3.83 (2H, d, J= 7.7 Hz), 3.77 (2H, d, J = 7.0 Hz), 3.18 (1H, d, J = 5.5 Hz), 3.17-3.25 (2H, m), 2.98 (1H, dd, J = 14.1, 7.9 Hz), 2.04 (1H, td, J = 11.3,3.8 Hz), 1.49 (2H, d, J = 11.0 Hz), 1.45-1.55 (1H, m), 1.26-1.36 (2H, m,J = 12.0, 12.0, 11.7, 3.8 Hz) 422.2 279

1H NMR (400 MHz, DMSO-d6) δ ppm 8.98 (1H, d, J = 7.7 Hz), 8.03 (1H, d, J= 8.1 Hz), 7.64 (1H, br. s.), 7.37 (1H, d, J = 8.1 Hz), 7.23 (1H, t, J =7.7 Hz), 7.11 (1H, br. s.), 7.15 (1H, t, J = 7.7 Hz), 6.97 (1H, s), 4.39(1H, d, J = 5.1 Hz), 3.80 (2 H, d, J = 8.1 Hz), 3.83 (1H, d, J = 7.7Hz), 3.77 (1H, br. s.), 3.24 (1H, br. s.), 3.23 (1H, d, J = 18.3 Hz),2.06 (1H, td, J = 11.1, 3.8 Hz), 1.67 (1H, dd, J = 11.9, 5.7Hz), 1.59(1H, d, J = 7.0 Hz), 1.53 (2 H, d, J = 11.7 Hz), 1.27-1.38 (2H, m), 0.88(2H, t, J = 6.0 Hz), 0.93 (5H, d, J = 59 Hz) 388.2 280

1H NMR (400 MHz, DMSO-d6) δ ppm 9.32 (1H, d, J = 8.1 Hz), 8.15 (1H, d, J= 8.1 Hz), 7.38 (1H, d, J = 7.7 Hz), 7.23 (1H, s), 7.28 (2H, dd, J =16.7, 5.5 Hz), 7.20 (2H, d, J = 11.0 Hz), 5.27-5.37 (1 H, m), 5.35 (1H,d, J = 4.0 Hz), 4.55 (1H, d, J = 4.4 Hz), 3.78 (3H, d, J = 7.3 Hz), 3.82(2H, d, J = 9.5 Hz), 3.20 (0H, br. s.), 3.24 (3H, t), 3.12 (1H, d, J =4.8 Hz), 2.85 (1H, d, J = 16.1 Hz), 2.00-2.11 (1 H, m), 1.52 (2H, d, J =12.1 Hz), 1.32 (2 H, dd), 1.29 (0H, d, J = 4.4 Hz) 407.2 281

1H NMR (400 MHz, DMSO-d6) δ ppm 8.74 (1H, d, J = 7.3 Hz), 8.06 (1H, d, J= 7.7 Hz), 7.36 (1H, d, J = 8,1 Hz), 7.23 (1H, t, J = 7.7 Hz), 7.15 (1H,t, J = 7.7 Hz), 4.82 (1H, d, J = 5.1 Hz), 3.78 (2H, d, J = 7.3 Hz),3.76-3.85 (2H, m), 3.36 (1H, dd, J = 8.4, 4.4 Hz), 3.23 (1H, br. s.),3.23 (1H, d, J = 19.4 Hz), 2.04 (2H, d, J = 5.1 Hz), 2.06 (1H, br. s.),1.88 (1H, dd, J = 9.1, 2.6 Hz), 1.58-1.68 (2H, m), 1.54 (1H, br. s.),1.50 (1H, d, J = 1.5 Hz), 1.33 (2H, d, J = 4.4 Hz), 1.27 (4H, d, J = 7.3Hz) 373.2 282

1H NMR (400 MHz, DMSO-d6) δ ppm 8.82 (1H, d, J = 9.9 Hz), 8.07 (1H, d, J= 8.1 Hz), 7.37 (1H, d, J = 7.7 Hz), 7.23 (1H, t, J = 7.7 Hz), 7.15 (1H,t, J = 7.7 Hz), 6.97 (1H, s), 4.65 (1H, t, J = 5.3 Hz), 3.78-3.86 (1H,m), 3.81 (3H, dd, J = 13.9, 7.3 Hz), 3.70 (1H, d, J = 8.8 Hz), 3.67 (1H,d, J = 7.0 Hz), 3.48 (1H, dd, J = 10.4, 5.7 Hz), 3.23 (2H, d, J = 10.6Hz), 2.07 (1H, dd, J = 10.6, 4.0 Hz), 1.53 (2H, d, J = 12.8 Hz),1.26-1.36 (1H, m), 1.33 (1H, d, J = 13.5 Hz), 0.96 (7H, s), 0.81 (2H, s)375.2 283

1H NMR (400 MHz, DMSO-d6) δ ppm 8.97 (1H, t, J = 5.3 Hz), 8.05 (1H, d, J= 7.7 Hz), 7.36 (1H, d, J = 7.7 Hz), 7.22 (1H, t, J = 7.7 Hz), 7.14 (1H,t, J = 7.7 Hz), 3.79 (3H, d, J = 7.3 Hz), 3.84 (1H, br. s.), 3.24 (3H,d, J = 5.5 Hz), 3.19 3.25 (1H, m), 2.25 (6H, s), 2.16 (2H, s), 2.02-2.11(1H, m), 1.53 (2H, d), 1.50 (0H, br. s.), 1.33 (0H, d, J = 4.0 Hz), 1.30(2H, d, J = 3.7 Hz), 0.90 (6H, s) 388.3 284

1H NMR (400 MHz, DMSO-d6) δ ppm 9.07 (1H, d, J = 8.4 Hz), 8.03 (1H, d, J= 7.7 Hz), 7.61 (1H, br. s.), 7.37 (1H, d, J = 7.7 Hz), 7.23 (1H, t, J =7.5 Hz), 7.12- 7.17 (2H, m), 4.28 (1H, dd, J = 8.2, 5.7 Hz), 3.85 (2H,br. s.), 3.82 (1H, d, J = 3.3 Hz), 3.79 (2H, d, J = 7.0 Hz), 3.18-3.26(2H, m), 2.07 (1H, dd, J = 8.8, 6.6 Hz), 1.78 (1H, br. s.), 1.63 (1H,br. s.), 1.70 (4H, t, J = 14.3 Hz), 1.53 (2H, d, J = 13.2 Hz), 1.37 (1H,br. s.), 1.33 (1H, d, J = 8.4 Hz) 1.17 (1H, d, J = 11.3 Hz), 1.20 (1H,br. s.), 1.02 (1H, d, J = 11.0 Hz), 1.05 (1 H, d, J = 10.6 Hz) 414.2 285

1H NMR (400 MHz, DMSQ-d6) δ ppm 0.99 (s, 8H) 1.28 (d, J = 3.76 Hz, 1H)1.34 (d, J = 4.83 Hz, 1H) 1.50 (d, J = 13.16 Hz, 2H) 1.96-2.11 (m, 1H)3.20 (t, J = 11.55 Hz, 2H) 3.81 (d, J = 3.76 Hz, 1H) 3.77 (d, J = 7.52Hz, 3H) 4.16 (d, J = 8.59 Hz, 1H) 7.13 (t, J = 8.32 Hz, 1 H) 7.22 (t, J= 7.12 Hz, 1H) 7.37 (d, J = 7.52 Hz, 1H) 7.99 (d, J = 7.25 Hz, 1H) 9.24(d, J = 8.59 Hz, 1H) 12.94 (br. s., 2 H) 389.2 286

1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (s, 7H) 1.33 (d, J = 9.15 Hz, 2H)1.51 (br. s., 2H) 2.08 (br. s., 1H) 3.16- 3.26 (m, 2H) 3.80 (d, J = 7.32Hz, 5H) 4.23 (d, J = 7.69 Hz, 1H) 7.16 (d, J = 7.69 Hz, 1H) 7.24 (t, J =7.69 Hz, 1H) 7.38 (d, J = 8.05 Hz, 1H) 8.03 (d, J = 8.05 Hz, 1H) 9.30(d, J = 7.69 Hz, 1H) 391.2 287

1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (d, J = 12.44 Hz, 6H) 1.32 (br. s.,1 H) 1.34 (d, J = 3.66 Hz, 1H) 1.52 (br. s., 2 H) 2.08 (br. s., 1H) 3.24(t, J = 11.53 Hz, 3H) 3.79 (d, J = 7.32 Hz, 4H) 4.25 (d, J = 8.05 Hz,1H) 7.15-7.25 (m, 3H) 7.37 (d, J = 8.05 Hz, 1H) 7.48 (br. s., 1H) 8.04(d, J = 8.05 Hz, 1H) 9.26 (d, J = 8.05 Hz, 1H) 390.2 288

1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (s, 3H) 1.18-1.23 (m, 3H) 1.25-1.37 (m, 3H) 1.53 (d, J = 12.44 Hz, 2H) 2.07 (td, J = 7.41, 3.48 Hz, 1H)3.18- 3.26 (m, 2H) 3.57 (dd, J = 10.98, 6.22 Hz, 1H) 3.74-3.85 (m, 1H)3.79 (q, J = 7.56 Hz, 5H) 4.55 (br. s., 1H) 7.15 (t, J = 7.32 Hz, 1H)7.23 (t, J = 7.14 Hz, 1H) 7.36 (d, J = 7.69 Hz, 1H) 8.08 (d, J = 7.69Hz, 1H) 8.91 (d, J = 9.15 Hz, 1H) 377.2 289

1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (s, 3H) 1.18-1.23 (m, 3H) 1.25-1.37 (m, 3H) 1.53 (d, J = 12.08 Hz, 2H) 2.06 (dt, J = 7.23, 3.89 Hz, 1H)3.17- 3.25 (m, 2H) 3.57 (dd, J = 10.80, 6.04 Hz, 1H) 3.74-3.85 (m, 3H)3.79 (d, J = 6.95 Hz, 3H) 4.57 (br. s., 1H) 7.15 (t, J = 7.32 Hz, 1H)7.23 (t, J = 7.32 Hz, 1H) 7.36 (d, J = 7.69 Hz, 1H) 8.08 (d, J = 7.69Hz, 1H) 8.90 (d, J = 9.15 Hz, 1H) 377.2 290

1H NMR (400 MHz, DMSO-d6) δ ppm 0.96 (s, 8H) 1.19-1.36 (m, J = 12.35,12.35, 12.22, 4.16 Hz, 2H) 1.49 (dd, J = 12.76, 2.28 Hz, 2H) 1.96-2.09(m, 1 H) 3.20 (t, J = 11.68 Hz, 2H) 3.80 (dd, J = 11.01, 3.49 Hz, 1H)3.75 (dd, J = 7.25, 1.07 Hz, 2H) 4.21 (d, J = 9.13 Hz, 1H) 7.07 (ddd, J= 9.67, 8.86, 2.69 Hz, 1H) 7.18 (s, 1H) 7.37 (dd, J = 8.86, 4.56 Hz, 1H)7.64 (s, 1H) 7.78 (dd, J = 9.67, 2.69 Hz, 1H) 9.13 (d, J = 8.86 Hz, 1H)406.2 291

1H NMR (400 MHz, DMSO-d6) δ ppm 0.94 (s, 12H) 1.52 (d, J = 12.05 Hz, 3H)3.24 (t, J = 11.16 Hz, 3H) 3.82 (d, J = 11.35 Hz, 3H) 3.78 (d, J = 7.32Hz, 3 H) 7.15 (s, 1H) 7.23 (s, 1H) 7.36 (s, 1 H) 8.04 (d, J = 8.05 Hz,1H) 8.78 (s, 1H) 403.2 292

1H NMR (400 MHz, DMSO-d6) δ ppm 9.19 (1H, d, J = 8.8 Hz), 8.04 (1H, d, J= 8.1 Hz), 7.62 (1H, br. s.), 7.28-7.35 (1H, m), 7.24 (1H, t, J = 7.5Hz), 7.14 (2 H, d, J = 5.9 Hz), 4.25 (1H, d, J = 9.1 Hz), 3.89-3.94 (2H,m), 3.88 (0H, br. s.), 1.67 (2H, t), 1.70 (0H, br. s.), 1.34 (1H, d, J =7.7 Hz), 1.29-1.39 (1H, m), 1.00 (9H, s), 0.93 (3H, d, J = 7.3 Hz), 0.90(1 H, br. s.) 346.2 293

1H NMR (400 MHz, DMSO-d6) δ ppm 0.96 (s, 7H) 1.13 (dd, J = 19.77, 6.59Hz, 2H) 1.88 (qd, J = 7.56, 7.32 Hz, 1H) 2.30-2.43 (m, 1H) 2.37 (d, J =8.05 Hz, 1H) 2.46 (br. s., 1H) 3.39 (d, J = 7.69 Hz, 1H) 3.94 (t, J =6.77 Hz, 2H) 4.21 (d, J = 9.15 Hz, 1H) 7.10 (d, J = 13.18 Hz, 1 H) 7.14(s, 1H) 7.21 (t, J = 7.69 Hz, 1H) 7.32 (d, J = 7.69 Hz, 1H) 7.57 (br.s., 1H) 8.01 (d, J = 7.69 Hz, 1H) 9.12 (d, J = 9.15 Hz, 1H) 400.2 294

1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (s, 9H) 1.27 (td, J = 11.80, 8.23Hz, 2H) 1.45 (d, J = 12.81 Hz, 2H) 2.00 (dd, J = 10.98, 5.86 Hz, 1H)3.22 (t, J = 11.35 Hz, 3H) 3.65 (d, J = 7.32 Hz, 2H) 3.68 (s, 1H) 3.82(d, J = 8.05 Hz, 2H) 7.03 (t, J = 8.78 Hz, 1H) 7.39 (t, J = 8.97 Hz, 1H)7.90 (br. s., 1H) 424.2 295

1H NMR (400 MHz, DMSO-d6) δ ppm 0.86 (s, 1H) 0.93 (s, 10H) 1.33 (br. s.,2 H) 1.53 (d, J = 12.08 Hz, 2H) 3.15-3.26 (m, 3H) 3.81 (br. s., 3H) 3.79(d, J = 6.95 Hz, 2H) 3.84 (br. s., 1H) 7.15 (s, 1H) 7.23 (s, 1H) 7.36(d, J = 7.69 Hz, 2H) 8.03 (s, 1H) 8.70 (s, 1H) 402.2 296

1H NMR (400 MHz, DMSO-d6) δ ppm 0.46 (d, J = 4.03 Hz, 1H) 0.44 (d, J =6.95 Hz, 1H) 0.77 (br. s., 1H) 0.79 (s, 7H) 0.91 (br. s., 1H) 0.88 (s,5H) 1.25 (br. s., 1H) 1.27 (d, J = 7.32 Hz, 1H) 1.44 (d, J = 15.01 Hz,3H) 2.39-2.48 (m, 2H) 3.18 (t, J = 10.43 Hz, 2H) 3.20 (br. s., 1 H) 3.63(6, J = 6.95 Hz, 1H) 3.70-3.79 (m, 1H) 3.76 (d, J = 3.29 Hz, 2H) 3.80(br. s., 1H) 6.93 (s, 2H) 7.10 (d, J = 8.78 Hz, 1H) 442.3 297

1H NMR (400 MHz, DMSO-d6) δ ppm 0.85 (s, 2H) 0.90 (s, 10H) 1.29 (br. s.,2 H) 1.49 (d, J = 12.44 Hz, 2H) 2.46 (6, J = 1.83 Hz, 2H) 3.10-3.20 (m,2H) 3.49 (d, J = 5.49 Hz, 1H) 3.54 (6, J = 5.86 Hz, 1H) 3.73 (br. s.,1H) 3.78 (dd, J = 11.90, 9.33 Hz, 3H) 7.10 (s, 2H) 7.19 (s, 1H) 7.31 (s,1H) 7.98 (d, J = 8.05 Hz, 1H) 8.05 (br. s., 1H) 8.72 (d, J = 9.52 Hz,1H) 459.2 298

1H NMR (400 MHz, DMSO-d6) δ ppm 9.21 (1H, d, J = 8.8 Hz), 8.25 (1H, d, J= 4.0 Hz), 8.03 (1H, d, J = 7.7 Hz), 7.37 (1H, d, J = 7.7 Hz), 7.23 (1H,t, J = 7.7 Hz), 7.15 (1H, t, J = 7.7 Hz), 4.20 (1H, d, J = 9.2 Hz), 3.84(1H, br. s.), 3.80 (3H, d, J = 7.7 Hz), 3.16-3.25 (2H, m), 2.66 (1 H,dd, J = 7.1, 3.5 Hz), 2.08 (1H, dd, J = 17.4, 3.1 Hz), 1.53 (2H, d, J =12.1 Hz), 1.33 (2H, d, J = 10.6 Hz), 1.28- 1.39 (1H, m), 0.96 (9H, s),0.63 (2H, d, J = 7.3 Hz), 0.40 (1H, br. s.), 0.42 (1H, d, J = 4.0 Hz)429.3 (M + H) 299

1H NMR (400 MHz, DMSO-d6) δ ppm 0.98 (s, 9H) 1.27 (s, 9H) 1.34 (d, J =12.08 Hz, 2H) 1.53 (d, J = 12.44 Hz, 2 H) 2.02-2.14 (m, 1H) 3.25 (s, 2H)3.82 (br. s., 1H) 3.79 (d, J = 7.32 Hz, 2H) 3.85 (br. s., 1H) 4.34 (d, J= 9.52 Hz, 1H) 7.14 (t, J = 7.69 Hz, 1H) 7.23 (t, J = 7.50 Hz, 1 H) 7.36(d, J 8.05 Hz, 1H) 7.78 (s, 1H) 8.05 (d, J = 8.05 Hz, 1H) 9.17 (d, J =9.15 Hz, 1H) 445.3 (M + H) 300

1H NMR (400 MHz, DMSO-d6) δ ppm 9.15 (1H, d, J = 9.2 Hz), 8.39 (1H, d, J= 7.3 Hz), 8.00 (1H, d, J = 8.1 Hz), 7.32 (1H, d, J = 8.1 Hz), 719 (1H,t, J = 7.5 Hz), 7.10 (1H, t, J = 7.7 Hz), 4.12-4.22 (1H, m), 4.21 (1H,d, J = 9.2 Hz), 3.80 (1 U, br. s.), 3.75 (2H, d, J = 7.3 Hz), 3.78 (1 H,br. s.), 3.20 (2H, br. s.), 2.11 (1H, d, J = 7.0 Hz), 2.14 (1H, br.s.),2.04 (1H, br. s.), 1.78-1.95 (2H, m), 1.60 (1H, d, J = 7.3 Hz),1.56-1.65 (1H, m), 1.49 (2 H, d, J = 12.1 Hz), 1.29 (2H, dd, J = 12.1,3.3 Hz), 0.93 (9H, s) 442.3 301

1H NMR (400 MHz, DMSO-d6) δ ppm 8.78 (1H, d, J = 9.5 Hz), 7.85 (1H, dd,J = 9.7, 2.4 Hz), 7.39 (1H, dd, J = 8.8, 4.8 Hz), 7.09 (1H, dd, J =18.3, 2.6 Hz), 4.66 (1H, t, J = 5.1 Hz), 3.84 (1H, br. s.), 3.81 (2H, d,J = 7.0 Hz), 3.79 (2H, d, J = 5.1 Hz), 3.69 (1H, dd, J = 6.6, 2.6 Hz),3.65 (1H, d, J = 4.4 Hz), 3.48 (1H, t, J = 11.3 Hz), 3.17-3.26 (2H, m),2.06 (1H, dd, J = 15.4, 5.9 Hz), 1.53 (2H, d, J = 12.1 Hz), 1.23-1.39(2H, in), 0.95 (9H, s) 393.2 302

1H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (1H, d, J = 8.4 Hz), 8.39 (1H, t, J= 4.8 Hz), 8.03 (1H, d, J = 7.7 Hz), 7.37 (1H, d, J = 7.7 Hz), 7.23 (1H,d, J = 8.4 Hz), 7.15 (1H, t, J = 7.9 Hz), 6.97 (1H, br. s.), 4.32 (1H,d, J = 8.4 Hz), 3.80 (3H, d, J = 7.7 Hz), 3.84 (1H, br. s.), 3.68 (2H,t, J = 5.1 Hz), 3.16-3.25 (2H, m), 2.08 (1 H, dd, J = 8.1, 2.9 Hz), 1.53(2H, d, J = 11.3 Hz), 1.33 (2H, qd, J = 12.2, 4.0 Hz), 1.01 (9H, s)445.2 303

1H NMR (400 MHz, DMSO-d6) δ ppm 9.22 (1H, d, J = 8.8 Hz), 8.12 (1H, d, J= 4.4 Hz), 8.03 (1H, d, J = 7.7 Hz), 7.37 (1H, d, J = 7.7 Hz), 7.23 (1H,t, J = 7.5 Hz), 7.15 (1H, t, J = 7.7 Hz), 4.24 (1H, d, J = 8.8 Hz),3.77-3.86 (3H, m), 3.84 (1 H, br. s.), 3.20-3.25 (1H, m), 2.61 (3H, d, J= 4.4 Hz), 2.00-2.16 (1H, m), 1.53 (2H, d, J = 12.4 Hz), 1.33-1.40 (1H,m), 1.23-1.33 (1H, m), 0.98 (9H, s) 393.2 304

1H NMR (400 MHz, DMSO-d6) δ ppm 9.18 (1H, d, J = 8.8 Hz), 8.05 (1H, d, J= 8.1 Hz), 7.62 (1H, br. s.), 7.36 (1H, d, J = 8.1 Hz), 7.23 (1H, t, J =7.5 Hz), 7.15 (2H, d, J = 8.4 Hz), 5.18 (1H, d, J = 16.5 Hz), 4.25 (1H,d, J = 8.8 Hz), 3.85 (2H, d, J = 2.6 Hz), 2.20 (2H, br. s.), 2.04- 2.14(2H, m), 1.90 (1H, br. s.), 1.77- 1.87 (1H, m), 1.41-1.56 (1H, m), 1.00(9H, s) 402.2 305

1H NMR (400 MHz, DMSO-d6) δ ppm 9.18 (1H, d, J = 9.2 Hz), 8.05 (1H, d, J= 8.1 Hz), 7.62 (1H, br. s.), 7.35 (1H, d, J = 8.1 Hz), 7.23 (1H, t, J =7.5 Hz), 7.14 (2H, d, J = 8.8 Hz), 5.18 (1H, d, J = 17.6 Hz), 4.25 (1H,d, J = 8.8 Hz), 3.85 (2H, d, J = 5.5 Hz), 2.20 (2H, br. s.), 2.04- 2.14(2H, m), 1.89 (1H, br. s.), 1.78- 1.87 (1H, m), 1.41-1.56 (1H, m), 1.00(9H, s) 402.2 306

1H NMR (400 MHz, DMSO-d6) δ ppm 9.18 (1H, d, J = 8.8 Hz), 8.05 (1H, d, J= 8.1 Hz), 7.62 (1H, br. s.), 7.37 (1H, d, J = 7.7 Hz), 7.24 (1H, t, J =7.5 Hz), 7.14 (2H, d, J = 8.1 Hz), 4.25 (1H, d, J = 8.8 Hz), 3.82 (2H,d, J = 7.0 Hz), 2.00 (3H, br. s.), 1.70-1.78 (3H, m), 1.30-1.39 (2H, m),1.00 (9H, s) 422.2 307

1H NMR (400 MHz, DMSO-d6) δ ppm 7.62 (1H, br. s.), 7.32 (1H, d, J = 8.4Hz), 7.14 (1H, d, J = 1.8 Hz), 4.24 (1H, d, J = 9.2 Hz), 3.72 (2H, dd, J= 7.0, 2.6 Hz), 3.24 (2H, s), 1.80 (1H, td, J = 6.8, 3.7 Hz), 1.66 (3H,dd, J = 5.3, 2.7 Hz), 1.61 (2H, br. s.), 1.14 (1H, br. s.), 1.16 (2H, d,J = 2.9 Hz), 0.99 (10H, s), 0.94 (2H, s) 464.1 308

1H NMR (400 MHz, DMSO-d6) δ ppm 8.74 (1H, d, J = 9.5 Hz), 7.32 (1H, d, J= 8.4 Hz), 4.65 (1H, t, J = 5.1 Hz), 3.71 (2H, d, J = 4.4 Hz), 3.67-3.74(1H, m), 3.65 (1H, d, J = 5.5 Hz), 3.49 (1H, d, J = 4.8 Hz), 1.81 (1H,d, J = 3.7 Hz), 1.63 (5H, d, J = 18.3 Hz), 1.15 (3H, d, J = 7.3 Hz),1.03 (2H, d, J = 11.3 Hz), 1.07 (1H, br. s.), 0.95 (9H, s), 0.82 (1H, s)451.2 309

1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (s, 8H) 1.31 (br. s., 2H) 1.51 (br.s., 2H) 2.18 (br. s., 1H) 3.21 (s, 1H) 3.28 (d, J = 10.98 Hz, 6H)3.76-3.86 (m, 4H) 4.14 (br. s., 1H) 7.15 (s, 1H) 7.23 (s, 1H) 7.35 (s,1H) 7.78 (br. s., 1H) 8.71 (d, J = 9.52 Hz, 1H) 416.2 310

1H NMR (400 MHz, DMSO-d6) δ ppm 0.41 (d, J = 9.52 Hz, 1H) 0.63 (d, J =7.32 Hz, 1H) 0.77 (d, J = 13.91 Hz, 2H) 0.90 (s. 4H) 0.96 (s, 6H) 1.29(dd, J = 7.32, 4.39 Hz, 2H) 1.33 (br. s., 1H) 1.45 (br. s., 1H) 1.53 (d,J = 11.71 Hz, 1H) 2.04 (br. s., 1H) 3.17-3.28 (m, 1H) 3.23 (d, J = 10.98Hz, 2H) 3.66 (d, J = 6.95 Hz, 1 H) 3.80 (d, J = 5.86 Hz, 1H) 3.77 (br.s., 1 H) 3.82 (br. s., 1H) 6.82 (d, J = 9.52 Hz, 1 H) 7.11 (t, J = 8.97Hz, 1H) 8.13 (s, 1H) 8.26 (d, J = 4.03 Hz, 1H) 446.2 311

1H NMR (400 MHz, DMSO-d6) δ ppm 8.82 (1H, t, J = 5.1 Hz), 8.06 (1H, d, J= 8.1 Hz), 7.35 (1H, d, J = 7.7 Hz), 7.23 (1H, t, J = 7.3 Hz), 7.15 (1H,t, J = 7.7 Hz), 6.01 (1H, s), 4.22 (2H, d, J = 5.5 Hz), 3.81 (2H, d, J =11.3 Hz), 3.76 (2H, 383.2 d, J = 7.0 Hz), 3.22 (1H, s), 3.22 (1H, d, J =19.4 Hz), 2.24 (3H, s), 2.17 (3H, s), 2.05 (1H, dd, J = 15.2, 7.5 Hz),1.49 (2 H, br. s.), 1.30 (1H, dd, J = 12.3, 3.5 Hz), 1.24-1.35 (1H, m)383.2 312

1H NMR (400 MHz, DMSO-d6) δ ppm 9.15 (1H, t, J = 5.7 Hz), 8.04 (1H, d, J= 7.7 Hz), 7.37 (1H, d, J = 7.7 Hz), 7.24 (1H, t, J = 7.7 Hz), 7.16 (1H,t, J = 7.5 Hz), 4.55 (2H, d, J = 5.5 Hz), 3.84 (2H, d, J = 2.2 Hz), 3.79(3H, d, J = 7.0 Hz), 3.19-3.24 (2H, m), 2.38 (3H, s), 2.07 (1H, dd, J =7.7, 3.7 Hz), 1.53 (2H, d, J = 11.7 Hz), 1.32 (2H, dd, J = 12.1, 4.0Hz), 1.26-1.37 (1H, m) 370.2 313

1H NMR (400 MHz, DMSO-d6) δ ppm 9.13 (1H, d, J = 8.8 Hz), 8.04 (1H, d, J= 7.7 Hz), 7.62 (1H, br. s.), 7.17-7.23 (2H, m), 7.08-7.17 (2H, m), 4.86(2H, s), 4.26 (1H, d, J = 8.8 Hz), 3.12 (3H, s), 3.09 (1H, br. s.), 2.86(3H, s), 2.84 (1 H, br. s.), 1.00 (8H, s), 0.94 (2H, s) 375.2 314

1H NMR (400 MHz, DMSO-d6) δ ppm 9.12 (1H, d, J = 8.8 Hz), 8.22 (1H, br.s.), 8.05 (1H, d, J = 7.3 Hz), 7.62 (1H, br. s.), 7.18 (1H, d, J = 8.8Hz), 7.15 (2H, d, J = 8.1 Hz), 6.92-6.99 (1H, m), 4.51 (2 H, s), 4.36(1H, s), 4.27 (1H, d, J = 8.8 Hz), 3.13-3.24 (1H, m), 3.11 (1H, d, J =6.6 Hz), 0.98-1.06 (10H, m), 0.94 (3 H, s) 375.2 315

1H NMR (400 MHz, DMSO-d6) δ ppm 9.08 (1H, d, J = 8.8 Hz), 7.63 (1H, br.s.), 7.12-7.22 (3H, m), 6.91-7.00 (1H, m), 5.09 (1H, s), 4.87 (1H, s),4.26 (1 H, d, J = 8.8 Hz), 2.24 (1H, br. s.), 0.99 (8 H, s), 1.03 (2H,d, J = 7.7 Hz), 0.94 (5H, s) 372.2 316

1H NMR (400 MHz, DMSO-d6) δ ppm 9.09 (1H, d, J = 9.2 Hz), 8.06 (1H, d, J= 7.7 Hz), 7.83 (1H, br. s.), 7.18 (1H, d, J = 4.4 Hz), 7.15 (2H, br.s.), 5.09 (2H, s), 4.27 (1H, d, J = 8.8 Hz), 1.25 (8H, s), 1.22 (1H, br.s.), 0.99 (9H, s), 0.94 (1 H, s) 388.2 317

1H NMR (400 MHz, DMSO-d6) δ ppm 9.21 (1H, d, J = 8.8 Hz), 8.18 (1H, t, J= 4.9 Hz), 8.04 (1H, d, J = 8.1 Hz), 7.36 (1H, d, J = 7.7 Hz), 7.23 (1H,t, J = 7.5 Hz), 7.14 (1H, t, J = 7.7 Hz), 4.60 (1H, t, J = 5.1 Hz), 4.30(1H, d, J = 8.8 Hz), 3.84 (1H, br. s.), 3.79 (3H, d, J = 7.7 Hz), 3.42(2H, q, J = 5.9 Hz), 3.20 (1H, br. s.), 3.23 (2H, d, J = 11.0 Hz), 3.13(1H, dt, J = 12.7, 6.3 Hz), 2.08 (1H, dd, J = 14.3, 7.0 Hz), 1.53 (2H,d, J = 12.1 Hz), 1.33 (2H, dd, J = 12.1, 3.3 Hz), 0.98 (9H, s) 432.2 318

1H NMR (400 MHz, DMSO-d6) δ ppm 9.21 (1H, d, J = 8.8 Hz), 8.16 (1H, t, J= 4.8 Hz), 8.04 (1H, d, J = 8.1 Hz), 7.36 (1H, d, J = 7.7 Hz), 7.23 (1H,t, J = 7.5 Hz), 7.15 (1H, t, J = 7.7 Hz), 4.38 (1H, t, J = 4.9 Hz), 4.26(1H, d, J = 8.8 Hz), 3.79 (3H, d, J = 7.7 Hz), 3.84 (1H, br. s.), 3.42(2H, d, J = 5.5 Hz), 3.19 (1H, br. s.), 3.23 (2H, d, J = 12.1 Hz), 3.07(1H, dt, J = 12.7, 6.3 Hz), 2.07 (1H, dt, J = 7.0, 3.5 Hz), 1.56 (3H,dd, J = 10.2, 2.6 Hz), 1.50- 1.60 (1H, m), 1.34 (1H, d, J = 3.3 Hz),1.32 (1H, br. s.), 0.98 (8H, s), 0.93 (1H, s) 446.3 319

1H NMR (400 MHz, DMSO-d6) δ ppm 9.42 (1H, d, J = 8.8 Hz), 8.01 (1H, d, J= 8.1 Hz), 7.39 (1H, d, J = 7.7 Hz), 7.25 (1H, t, J = 7.7 Hz), 7.16 (1H,1, J = 7.7 Hz), 7.01 (2H, s), 4.87 (1H, d, J = 8.4 Hz), 3.80 (3H, d, J =7.7 Hz), 3.84 (1H, br. s.), 3.19-3.25 (2H, m), 2.07 (1H, dd, J = 10.4,3.5 Hz), 1.54 (2H, d, J = 12.8 Hz), 1.34 (1H, d, J = 2.9 Hz), 1.28 (1H,d, J = 6.6 Hz), 1.32 (1H, br. s.), 1.03 (9H, s) 428.2 320

1H NMR (400 MHz, DMSO-d6) δ ppm 9.09 (1H, t, J = 5.9 Hz), 803 (1H, d, J= 7.7 Hz), 7.36 (1H, d, J = 7.3 Hz), 7.24 (1H, t, J = 7.7 Hz), 7.15 (1H,t, J = 7.9 Hz), 6.37 (1H, s), 4.47 (2H, d, J = 4.8 Hz), 3.82 (2H, dd, J= 11.5, 2.7 Hz), 3.78 (2H, d, J = 7.3 Hz), 3.19-3.26 (2H, m), 2.30 (3H,s), 2.05 (1H, td, J = 7.4, 3.8 Hz), 1.53 (2H, d, J = 12.8 Hz), 1.26-1.37 (2H, m, J = 12.4, 12.4, 11.9, 4.4 Hz) 437.2 321

1H NMR (400 MHz, DMSO-d6) δ ppm 9.29 (1H, t, J = 5.7 Hz), 8.02 (1H, d, J= 7.7 Hz), 7.38 (1H, d, J = 8.1 Hz), 7.25 (1H, t, J = 7.3 Hz), 7.17 (1H,d, J = 7.0 Hz), 6.95-7.02 (1H, m), 4.78 (1H, d, J = 5.5 Hz), 4.49 (1H,t, J = 4.9 Hz), 4.39 (1H, d, J = 5.9 Hz), 4.43 (1H, t, J = 6.4 Hz), 3.80(4H, d, J = 7.0 Hz), 3.84 (1H, 3.26 (4H, m), 2.89 (1H, td, J = 12.7, 3.1Hz), 2.08 (1H, td, J = 7.5, 3.7 Hz), 1.81 (1H, br. s.), 1.70 (1H, t, J =8.4 Hz), 1.66- 1.77 (1H, m), 1.47 (1H, d, J = 12.4 Hz), 1.54 (2H, d, J =12.8 Hz), 1.32 (1H, dd, J = 12.6, 4.2 Hz), 1.26-1.37 (1H, m), 1.09-1.19(1H, m), 1.14 (1H, d, J = 10.2 Hz) 498.2 322

1H NMR (400 MHz, DMSO-d6) δ ppm 1.23-1.34 (m, J = 12.21, 12.21, 11.99,4.21 Hz, 2H) 1.49 (br. s., 1H) 1.52 (d, J = 1.83 Hz, 1H) 2.04 (ddd, J =11.35, 7.50, 4.21 Hz, 1H) 2.26 (s, 3H) 3.21 (t, J = 10.98 Hz, 2H) 3.70(s, 3H) 3.74- 3.83 (m, 2H) 3.75 (d, J = 7.32 Hz, 3H) 4.30 (d, J = 5.49Hz, 2H) 7.15 (t, J = 7.87 Hz, 1H) 7.22 (t, J = 7.32 Hz, 1H) 7.33- 7.37(m, 2H) 8.06 (d, J = 8.05 Hz, 1H) 8.79 (s, 1H) 383.2 323

1H NMR (400 MHz, DMSO-d6) δ ppm 9.34 (1H, br. s.), 9.29 (1H, t, J = 5.9Hz), 8.02 (1H, d, J = 8.1 Hz), 7.38 (1H, d, J = 7.7 Hz), 7.25 (1H, t, J= 7.3 Hz), 7.16 (1H, t, J = 7.7 Hz), 4.78 (2H, d, J = 5.5 Hz), 3.80 (3H,d, J = 7.3 Hz), 3.84 (1H, d, J = 2.9 Hz), 3.23 (1H, d, J = 13.9 Hz),3.25 (2H, d, J = 8.1 Hz), 2.07 (1H, ddd, J = 11.3, 7.2, 3.8 Hz), 1.54(2H, d, J = 11.7 Hz), 1.51-1.61 (1H, m), 1.42 (3H, q, J = 7.0 Hz), 1.32(2H, dd, J = 12.8, 4.0 Hz), 0.89 (3H, s), 0.89 (2H, d, J = 6.6 Hz, 0.87(2H, s) 470.2 324

1H NMR (400 MHz, DMSO-d6) δ ppm 9.22 (1H, t, J = 5.9 Hz), 8.03 (1H, d, J= 8.1 Hz), 7.38 (1H, d, J = 8.1 Hz), 7.25 (1H, t, J = 7.1 Hz), 7.17 (1H,d, J = 8.1 Hz), 4.67 (2H, d, J = 5.9 Hz), 4.33-4.44 (1H, m), 3.80 (3H,d, J = 7.3 Hz), 3.75- 3.85 (2H, m), 3.20-3.26 (1H, m), 3.25 (1H, d, J =8.8 Hz), 2.06 (1H, ddd, J = 11.3, 7.7, 4.0 Hz), 1.47-1.56 (2H, m), 1.32(5H, d, J = 7.0 Hz), 1.29-1.36 (2H, m) 399.2 325

1H NMR (400 MHz, DMSO-d6) δ ppm 10.77 (1H, br. s.), 9.92-9.98 (1H, m),8.55 (1H, s), 8.47 (1H, d, J = 3.3 Hz), 7.74 (1H, d, J = 8.1 Hz), 7.36(1H, q, J = 7.8 Hz), 7.14 (1H, d, J = 5.9 Hz), 6.96- 7.01 (2H, m), 4.48(2H, d, J = 4.8 Hz), 4.39 (1H, d, J = 5.9 Hz), 4.44 (1H, d, J = 6.2 Hz),3.80-3.84 (1H, m), 3.82 (1 H, d, J = 13.9 Hz), 3.67 (2H, d, J = 7.3 Hz),3.25 (1H, br. s.), 3.22 (1H, s), 3.22 H, t, J = 10.6 Hz), 2.02 (1H, ddd,J = 11.3, 7.3, 3.7 Hz), 1.46 (2H, t, J = 13.0 Hz), 1.42-1.52 (1H, m),1.29 (2H, td, J = 12.1, 4.0 Hz) 398.3 (M + H) 326

1H NMR (400 MHz, DMSO-d6) δ ppm 9.05 (1H, t, J = 5.7 Hz), 8.05 (1H, d, J= 7.0 Hz), 7.36 (1H, d, J = 7.7 Hz), 7.24 (1H, t, J = 7.7 Hz), 7.16 (1H,t, J = 7.9 Hz), 4.46 (2H, d, J = 5.5 Hz), 3.82 (2H, dd, J = 11.3, 2.6Hz), 3.78 (2H, d, J = 7.0 Hz), 3.18-3.26 (3H, m), 1.99-2.11 (1 H, m, J =11.3, 7.5, 3.8, 3.8 Hz), 1.54 (1 H, d, J = 1.5 Hz), 1.51 (2H, br. s.),1.31 (2 H, qd, J = 12.2, 4.4 Hz) 356.2 327

1H NMR (400 MHz, DMSO-d6) δ ppm 9.22 (1H, t, J = 5.7 Hz), 8.03 (1H, d, J= 7.7 Hz), 7.38 (1H, d, J = 7.7 Hz), 7.25 (1H, t, J = 7.7 Hz), 7.16 (1H,t, J = 7.9 Hz), 4.67 (2H, d, J = 5.9 Hz), 3.80 (3H, d, J = 7.3 Hz), 3.84(1H, d, J = 2.9 Hz), 3.19-3.26 (2H, m), 2.94 (2H, q, J = 7.4 Hz), 2.07(1H, td, J = 7.5, 3.7 Hz), 1.53 (2H, d, J = 12.4 Hz), 1.28 (4H, t, J =7.5 Hz), 1.25-1.37 (1H, m) 385.2 328

1H NMR (400 MHz, DMSO-d6) δ ppm 9.13 (1H, t, J = 5.5 Hz), 8.05 (1H, d, J= 8.1 Hz), 7.34-7.39 (2H, m), 7.24 (1 H, t, J = 7.7 Hz), 7.15 (1H, t, J= 7.9 Hz), 4.58 (2H, d, J = 5.5 Hz), 3.82 (2H, dd, J = 11.5, 2.7 Hz),3.78 (2H, d, J = 7.3 Hz), 3.19-3.26 (2H, m), 2.98 (2H, q, J = 7.7 Hz),2.06 (1H, td, J = 7.5, 3.7 Hz), 1.53 (2H, d, J = 11.3 Hz), 1.30 (4H, 1,J = 7.5 Hz), 1.26-1.37 (1H, m) 400.2 329

1H NMR (400 MHz, DMSO-d6) δ ppm 8.93 (1H, t, J = 5.5 Hz), 8.06 (1H, d, J= 8.1 Hz), 7.63 (1H, d, J = 14.6 Hz), 7.36 (1H, d, J = 7.7 Hz), 7.23(1H, t, J = 7.1 Hz), 7.16 (1H, t, J = 7.9 Hz), 6.52 (1H, s), 4.37 (2H,d, J = 5.5 Hz), 3.77 (2H, d, J = 7.3 Hz), 3.74-3.84 (3H, m), 3.22 (1 H,t, J = 10.8 Hz), 3.24 (1H, d, J = 15.7 Hz), 2.05 (1H, ddd, J = 11.3,7.6, 3.8 Hz), 1.53 (1H, d, J = 1.8 Hz), 1.50 (1H, br. s.), 1.25-1.36(2H, m, J = 12.3, 12.3, 12.0, 4.4 Hz) 555.2 330

1H NMR (400 MHz, DMSO-d6) δ ppm 9.30 (1H, t, J = 5.7 Hz), 9.38 (1H, t, J= 5.7 Hz), 8.03 (1H, d, J = 8.1 Hz), 7.39 (1H, d, J = 7.7 Hz), 7.25 (1H,t, J = 7.9 Hz), 7.13-7.20 (1H, m), 7.19 (4H, d, J = 2.9 Hz), 4.91 (1H,dd, J = 8.4, 3.3 Hz), 4.79 (2H, d, J = 5.5 Hz), 4.03 (1H, dt, J = 11.3,5.5 Hz), 3.81 (3H, d, J = 7.3 Hz), 3.84 (1H, br. s.), 3.62-3.74 (4H, m),3.19-3.26 (2H, m), 2.71-2.81 (2H, m), 2.07 (1H, dd, J = 11.3, 7.3 Hz),1.53 (1H, d, J = 1.5 Hz), 1.46-1.57 (1H, m), 1.27-1.38 (2H, m, J = 12.4,12.4, 12.1, 4.6 Hz) 546.2 331

1H NMR (400 MHz, DMSO-d6) δ ppm 9.29 (1H, t, J = 5.7 Hz), 8.02 (1H, d, J= 8.1 Hz), 7.38 (1H, d, J = 8.1 Hz), 7.25 (1H, t, J = 7.7 Hz), 7.16 (1H,t, J = 7.9 Hz), 4.78 (2H, d, J = 5.9 Hz), 3.80 (3H, d, J = 7.0 Hz), 3.84(1H, d, J = 2.6 Hz), 3.61 (1H, d, J = 6.2 Hz), 3.58-3.68 (1H, m), 3.49(2H, t, J = 6.0 Hz), 3.19-3.26 (2 H, m), 2.07 (1H, td, J = 7.3, 3.3 Hz),1.64- 1.75 (2H, m), 1.64-1.75 (2H, m, J = 5.8, 5.8, 5.8, 5.8 Hz), 1.50(1H, br. s.), 1.53 (5H, d, J = 10.2 Hz), 1.32 (1H, dd, J = 13.2, 4.4Hz), 1.26-1.37 (1H, m) 482.2 332

1H NMR (400 MHz, DMSO-d6) δ ppm 9.29 (1H, t, J = 5.9 Hz), 9.26-9.35 (1H,m), 8.02 (1H, d, J = 8.1 Hz), 7.38 (1H, d, J = 7.7 Hz), 7.25 (1H, t, J =7.3 Hz), 7.16 (1H, t, J = 8.4 Hz), 6.94-7.05 (1H, m), 4.78 (1H, d, J =5.9 Hz), 3.80 (3H, d, J = 7.3 Hz), 3.84 (1H, d, J = 2.9 Hz), 3.31- 3.36(1H, m), 3.17-3.26 (6H, m), 2.19 (2H, t, J = 7.9 Hz), 2.08 (1H, dt, J =7.5, 3.9 Hz), 1.91 (1H, d, J = 7.3 Hz), 1.86- 1.96 (1H, m), 1.67-1.76(2H, m, J = 7.0, 7,0, 7.0, 7.0 Hz), 1.54 (2H, d, J = 11.0 Hz), 1.32 (2H,dd, J = 12.6, 4.2 Hz), 1.26- 1.37 (1H, m) 525.2 333

1H NMR (400 MHz, DMSO-d6) δ ppm 8.88 (1H, t, J = 5.5 Hz), 8.07 (1H, d, J= 8.1 Hz), 7.71 (1H, s), 7.42 (1H, s), 7.35 (1H, d, J = 7.7 Hz), 7.23(1H, t, J = 7.3 Hz), 7.15 (1H, t, J = 7.7 Hz), 4.36 (2H, d, J = 5.9 Hz),4.09 (2H, q, J = 7.3 Hz), 3.81 (2H, dd, J = 11.5, 2.7 Hz), 3.76 (2H, d,J = 7.3 Hz), 3.22 (2H, t, J = 10.8 Hz), 2.04 (1H, td, J = 7.6, 3.8 Hz),1.51 (2H, d, J = 11.0 Hz), 1.29 (2H, dd, J = 12.6, 4.2 Hz), 1.34 (3H, t,J = 7.1 Hz) 383.2 334

1H NMR (400 MHz, DMSO-d6) δ ppm 9.72 (1H, d, J = 8.4 Hz), 9.29 (1H, t, J= 5.9 Hz), 7.38 (1H, d, J = 7.7 Hz), 7.25 (1H, t, J = 7.7 Hz), 7.10-7.21(5H, m), 6.94-7.05 (1H, m), 5.19 (1H, br. s.), 4.78 (1H, d, J = 5.9 Hz),3.79 (4H, d, J = 7.3 Hz), 3.19-3.26 (2H, m), 2.74 (2 H, d, J = 4.8 Hz),2.05 (1H, d, J = 8.1 Hz), 1.97 (2H, br. s.), 1.89 (1H, d, J = 8.8 Hz),1.74 (1H, br. s.), 1.52 (2H, br. s.), 1.32 (2H, d, J = 7.0 Hz),1.26-1.37 (1H, m) 530.2 335

1H NMR (400 MHz, DMSO-d6) δ ppm 9.29 (1H, t, J = 5.7 Hz), 8.02 (1H, d, J= 7.7 Hz), 7.38 (1H, d, J = 7.7 Hz), 7.25 (1H, t, J = 7.9 Hz), 7.16 (1H,t, J = 8.2 Hz), 6.97 (1H, s), 4.79 (2H, d, J = 5.5 Hz), 3.80 (4H, d, J =7.3 Hz), 3.84 (1H, br. s.), 3.24 (1H, d, J = 1.5 Hz), 3.22 (1H, d, J =6.2 Hz), 3.11 (3H, s), 3.04 (3H, s), 2.07 (1H, ddd, J = 11.3, 7.2, 3.8Hz), 1.54 (2H, d, J = 1 2.4 Hz), 1.32 (2H, dd, J = 12.6, 4.2 Hz),1.26-1.37 (1H, m) 428.2 336

1H NMR (400 MHz, DMSO-d6) δ ppm 9.29 (1H, t, J = 5.9 Hz), 8.02 (1H, d, J= 7.7 Hz), 7.35 (1H, d, J = 8.1 Hz), 7.25 (1H, t, J = 7.7 Hz), 7.16 (1H,t, J = 8.2 Hz), 6.97 (1H, s), 4.78 (2H, d, J = 5.9 Hz), 3.80 (3H, d, J =7.3 Hz), 3.84 (1H, br. s.), 3.67 (1H, d, J = 7.3 Hz), 3.40- 3.48 (4H,m), 3.20-3.26 (5H, m), 2.06 (1H, ddd, J = 18.1, 10.8, 3.7 Hz), 1.47 (1H, d, J = 14.3 Hz), 1.52 (1H, br. s.), 1.32 (2H, dd, J = 12.6, 4.6 Hz),1.26-1.37 (1 H, m) 458.2 337

1H NMR (400 MHz, DMSO-d6) δ ppm 9.09 (1H, t, J = 5.7 Hz), 8.04 (1H, d, J= 7.7 Hz), 7.35 (1H, d, J = 7.7 Hz), 7.23 (1H, t, J = 7.3 Hz), 7.15 (1H,t, J = 7.7 Hz), 4.60 (2H, d, J = 5.9 Hz), 3.81 (3H, dd, J = 11.5, 3.1Hz), 3.76 (2H, d, J = 7.0 Hz), 3.22 (2H, t, J = 11.0 Hz), 3.26 (1H, br.s.), 2.34 (3H, s), 1.99-2.09 (1H, m, J = 11.1, 7.4, 3.8, 3.7 Hz), 1.51(2H, d, Hz), 1.30 (2H, dd, J = 12.6, 4.2 Hz) 400.2 338

1H NMR (400 MHz, DMSO-d6) δ ppm 9.29 (2H, t, J = 5.7 Hz), 8.02 (1H, d, J= 7.7 Hz), 7.38 (1H, d, J = 7.7 Hz), 7.25 (1H, t, J = 7.3 Hz), 7.16 (1H,t, J = 8.2 Hz), 4.78 (1H, d, J = 5.9 Hz), 3.80 (3H, d, J = 7.3 Hz), 3.84(1H, d, J = 3.7 Hz), 3.19-3.26 (1H, m), 3.24 (1H, d, J = 1.5 Hz), 2.79(3H, d, J = 4.8 Hz), 2.07 (1H, td, J = 7.5, 3.7 Hz), 1.54 (2H, d, J =12.4 Hz), 1.42 (1H, s), 1.32 (1H, dd, J = 12.8, 4.4 Hz), 1.26-1.37 (1H,m) 414.2 339

1H NMR (400 MHz, DMSO-d6) δ ppm 8.87 (1H, t, J = 5.5 Hz), 8.07 (1H, d, J= 7.7 Hz), 7.73 (1H, s), 7.35 (1H, d, J = 7.7 Hz), 7.23 (1H, t, J = 7.3Hz), 7.15 (1H, t, J = 8.2 Hz), 4.45 (1H, dt, J = 13.3, 6.7 Hz), 4.36(2H, d, J = 5.5 Hz), 3.81 (2 H, dd, J = 11.5, 2.7 Hz), 3.76 (2H, d, J =7.3 Hz), 3.22 (2H, t, J = 10.6 Hz), 2.04 (1H, ddd, J = 11.3, 7.4, 3.7Hz), 1.51 (2 H, d, J = 11.3 Hz), 1.39 (6H, d, J = 7.0 Hz), 1.30 (1H, t,J = 12.3 Hz), 1.30 (1H, q, J = 12.1 Hz) 397.2 340

1H NMR (400 MHz, DMSO-d6) δ ppm 9.32 (1H, t, J = 5.9 Hz), 8.04 (1H, dd,J = 7.9, 3.5 Hz), 7.39 (1H, d, J = 8.1 Hz), 7.15-7.23 (3H, m), 6.96-7.04(1H, m), 4.85 (1H, s), 4.82 (2H, d, J = 5.1 Hz), 4.42 (1H, d, J = 5.5Hz), 3.77-3.89 (6H, m), 3.67 (1H, d, J = 7.0 Hz), 3.19- 3.26 (3H, m),2.89 (1H, d, J = 5.9 Hz), 2.92 (1H, t, J = 6.0 Hz), 2.34 (1H, s), 2.06(1H, td, J = 11.1, 7.1 Hz), 1.52 (2H, t, J = 11.7 Hz), 1.32 (1H, d, J =14.3 Hz), 1.25-1.36 (1H, m) 383.2 341

1H NMR (400 MHz, DMSO-d6) δ ppm 9.12 (1H, t, J = 5.5 Hz), 8.05 (1H, d, J= 7.7 Hz), 7.34-7.41 (2H, m), 7.24 (1 H, t, J = 7.3 Hz), 7.16 (1H, t, J= 7.9 Hz), 4.57 (2H, d, J = 5.5 Hz), 3.82 (2H, dd, J = 11.7, 2.6 Hz),3.78 (2H, d, J = 7.3 Hz), 3.23 (1H, s), 3.23 (1H, t, J = 10.8 Hz), 2.65(3H, s), 2.06 (1H, ddd, J = 11.2, 7.3, 3.8 Hz), 1.53 (2H, d, J = 11.0Hz), 1.31 (2H, dd, J = 12.8, 4.0 Hz), 1.26- 1.37 (1H, m) 387.2 (M + H)342

1H NMR (400 MHz, DMSO-d6) δ ppm 9.28 (1H, t, J = 5.7 Hz), 9.21 (1H, d, J= 8.1 Hz), 8.23 (1H, none), 8.02 (1H, d, J = 7.7 Hz), 7.38 (1H, d, J =7.7 Hz), 7.25 (1H, t, J = 7.9 Hz), 7.16 (1H, t, J = 8.2 Hz), 6.95-7.01(1H, m), 4.77 (1 H, d, J = 5.9 Hz), 4.52 (1H, d, J = 4.4 Hz), 3.80 (3H,d, J = 7.3 Hz), 3.83 (1H, d, J = 7.0 Hz), 3.67 (1H, d, J = 7.3 Hz),3.65- 3.74 (1H, m), 3.36 (1H, td, J = 11.0, 4.0 Hz), 3.19-3.26 (2H, m),2.07 (1H, ddd, J = 8.4, 4.8, 4.4 Hz), 1.74-1.86 (4H, m), 1.55 (2H, br.s.), 1.45 (3H, t, J = 12.8 Hz), 1.32 (1H, dd, J = 12.3, 4.2 Hz), 1.22(2H, d, J = 12.8 Hz), 1.27 (1H, br..s.) 498.2 343

1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (1H, t, J = 5.3 Hz), 8.06 (1H, d, J= 7.7 Hz), 7.35 (1H, d, J = 7.7 Hz), 7.22 (1H, t, J = 7.1 Hz), 7.15 (1H,t, J = 7.7 Hz), 4.28 (2H, d, J = 5.1 Hz), 3.75 (3H, d, J = 7.3 Hz),3.73-3.84 (3H, m), 3.21 (2H, t, J = 10.8 Hz), 2.18 (5H, br. s.), 2.03(1H, ddd, J = 11.1, 7.4, 3.8 Hz), 1.51 (1H, d, J = 1.5 Hz), 1.48 (1H,br. s.), 1.28 (2H, qd, J = 12.2, 4.4 Hz) 384.2 (M + H) 344

1H NMR (400 MHz, DMSO-d6) δ ppm 8.88 (1H, t, J = 5.5 Hz), 8.06 (1H, d, J= 7.7 Hz), 7.67 (1H, s), 7.35 (1H, d, J = 7.7 Hz), 7.41 (1H, s), 7.23(1H, t, J = 7.1 Hz), 7.15 (1H, t, J = 8.2 Hz), 4.35 (2H, d, J = 5.5 Hz),3.75-3.83 (7H, m), 3.22 (2H, t, J = 10.6 Hz), 2.04 (1H, ddd, J = 11.1,7.4, 3.8 Hz), 1.53 (1H, br. s.), 1.49 (1H, d, J = 1.8 Hz), 1.24-1.34(2H, m, J = 1 2.3, 12.3, 12.0, 4.4 Hz) 369.2 345

1H NMR (400 MHz, DMSO-d6) δ ppm 9.21 (1H, d, J = 9.2 Hz), 8.14 (1H, br.s.), 8.04 (1H, d, J = 8.1 Hz), 7.37 (1H, d, J = 7.7 Hz), 7.23 (1H, t, J= 7.7 Hz), 7.15 (1H, t, J = 7.7 Hz), 4.63 (1H, d, J = 4.8 Hz), 4.47 (1H,t, J = 5.5 Hz), 4.34 (1H, d, J = 8.8 Hz), 3.79 (3H, d, J = 7.7 Hz), 3.84(1H, br. s.), 3.52 (1H, d, J = 5.1 Hz), 3.30- 3.36 (2H, m), 3.15-3.25(2H, m), 2.97 (1H, ddd, J = 12.8, 6.2, 5.9 Hz), 2.08 (1H, dd, J = 11.2,5.3 Hz), 1.53 (2H, d, J = 12.4 Hz), 1.33 (1H, d, J = 14.6 Hz), 1.28-1.38(1H, m), 0.99 (9H, s) 462.3 346

1H NMR (400 MHz, DMSO-d6) δ ppm 9.28 (1H, t, J = 5.9 Hz), 8.04 (1H, d, J= 7.7 Hz), 7.40 (1H, d, J = 7.7 Hz), 7.27 (1H, t, J = 7.1 Hz), 7.18 (1H,t, J = 7.3 Hz), 4.78 (2H, d, J = 5.9 Hz), 3.82 (3H, d, J = 7.3 Hz), 3.86(2H, d, J = 2.9 Hz), 3.25 (1H, s), 3.25 (2H, t, J = 11.0 Hz), 2.52 (1H,br. s.), 2.09 (1H, ddd, J = 11.2, 7.5, 4.0 Hz), 1.54 (2H, br. s.), 1.34(2H, qd, J = 12.2, 4.4 Hz) 371.2 347

1H NMR (400 MHz, DMSO-d6) δ ppm 9.38 (1H, d, J = 8.8 Hz), 7.79 (1H, dd,J = 9.5, 2.6 Hz), 7.41 (1H, dd, J = 8.8, 4.8 Hz), 7.11 (1H, td, J = 9.1,2.6 Hz), 7.03 (2 H, s), 4.87 (1H, d, J = 8.8 Hz), 3.81 (3H, br. s.),3.79 (2H, d, J = 7.3 Hz), 3.74 (1H, d, J = 7.0 Hz), 3.19-3.26 (3H, m),2.05 (1H, td, J = 11.8, 4.6 Hz), 1.54 (2H, d, J = 12.4 Hz), 1.32 (2H,dd, J = 12.4, 4.0 Hz), 1.03 (8H, s) 446.2 348

1H NMR (400 MHz, DMSO-d6) δ ppm 9.19 (1H, d, J = 8.8 Hz), 8.06 (1H, d, J= 7.3 Hz), 7.63 (1H, br. s.), 7.32-7.39 (4H, m), 7.30 (1H, d, J = 6.6Hz), 7.20- 7.27 (1H, m), 7.15 (2H, d, J = 5.5 Hz), 7.17 (1H, d, J = 7.0Hz), 5.13 (2H, d, J = 4.8 Hz), 4.27 (1H, d, J = 8.8 Hz), 1.01 (9H, s),0.93 (1H, s) 380.2 349

1H NMR (400 MHz, DMSO-d6) δ ppm 9.36 (1H, t, J = 5.9 Hz), 8.01 (1H, d, J= 7.7 Hz), 7.37 (1H, d, J = 7.7 Hz), 7.25 (1H, t, J = 7.7 Hz), 7.15 (1H,t, J = 8.2 Hz), 6.97 (1H, s), 4.82 (2H, d, J = 5.5 Hz), 3.78 (2H, d, J =7.0 Hz), 3.82 (1H, d, J = 11.7 Hz), 3.67 (1H, d, J = 7.3 Hz), 3.23 (2H,t, J = 10.8 Hz), 2.57-2.65 (3 H, m), 2.05 (1H, dd, J = 11.7, 7.7 Hz),1.47 (1H, d, J = 12.8 Hz), 1.53 (1H, d, J = 11.7 Hz), 1.32 (1H, d, J =12.8 Hz), 1.31 (1H, q, J = 12.3 Hz) 454.1 350

1H NMR (400 MHz, DMSO-d6) δ ppm 9.15 (1H, d, J = 7.3 Hz), 8.05 (1H, d, J= 7.7 Hz), 7.38 (1H, s), 7.36 (1H, d, J = 8.4 Hz), 7.23 (1H, t, J = 7.3Hz), 7.15 (1H, t, J = 7.9 Hz), 5.15 (1H, t, J = 7.1 Hz), 3.82 (2H, d, J= 11.0 Hz), 3.77 (2H, d, J = 7.3 Hz), 3.23 (2H, t, J = 11.3 Hz), 2.66(3H, s), 2.05 (1H, ddd, J = 7.5, 4.0, 3.8 Hz), 1.52 (5H, d, J = 7.0 Hz),1.31 (2 H, dd, J = 11.9, 3.5 Hz), 1.26-1.36 (1H, m) 401.2 (M + H) 351

1H NMR (400 MHz, DMSQ-d6) δ ppm 9.15 (1H, d, J = 8.8 Hz), 8.05 (1H, d, J= 7.7 Hz), 7.63 (1H, br. s.), 7.38 (1H, d, J = 7.7 Hz), 7.25 (1H, t, J =7.3 Hz), 7.16 (2H, d, J = 8.8 Hz), 7.19 (1H, s), 4.89 (1 H, dd, J = 6.4,3.5 Hz), 4.26 (1H, d, J = 9.1 Hz), 4.16 (1H, d, J = 4.0 Hz), 4.12-4.21(1H, m), 2.34 (1H, dd, J = 13.2, 7.0 Hz), 2.03 (1H, dd, J = 11.0, 9.1Hz), 1.00 (10 H, s) 388.2 352

1H NMR (400 MHz, DMSO-d6) δ ppm 9.38 (1H, d, J = 8.4 Hz), 8.02 (1H, d, J= 8.1 Hz), 7.40 (1H, d, J = 7.3 Hz), 7.26 (1H, t, J = 7.7 Hz), 7.18 (1H,t, J = 7.7 Hz), 7.03 (2H, s), 4.88 (2H, d, J = 8.8 Hz), 4.11-4.26 (2H,m), 2.56 (1H, s), 2.35 (1H, dd, J = 12.8, 7.0 Hz), 1.97- 2.08 (1H, m),1.03 (10H, s) 428.2 353

1H NMR (400 MHz, DMSO-dB) δ ppm 9.17 (1H, d, J = 8.8 Hz), 8.18 (1H, t, J= 5.3 Hz), 8.05 (1H, d, J = 7.7 Hz), 7.38 (1H, d, J = 7.3 Hz), 7.24 (1H,t, J = 7.7 Hz), 7.17 (1H, t, J = 7.9 Hz), 4.89 (1H, dd, J = 7.3, 4.0Hz), 4.38 (1H, t, J = 4.9 Hz), 4.27 (1H, d, J = 8.8 Hz), 4.17 (1H, d, J= 9.9 Hz), 4.11-4.21 (1H, m), 3.42 (1H, d, J = 5.1 Hz), 3.42 (1H, d, J =17.2 Hz), 3.20 (1H, dt, J = 13.4, 6.6 Hz), 3.07 (1H, dt, J = 12.8, 6.4Hz), 2.34 (1H, d, J = 5.9 Hz), 2.29-2.41 (1H, m), 1.97- 2.09 (1H, m),1.58 (2H, td, J = 6.7, 2.0 Hz), 0.98 (10H, s) 446.2 354

1H NMR (400 MHz, DMSO-d6) δ ppm 9.18 (1H, d, J = 8.8 Hz), 8.20 (1H, t, J= 5.3 Hz), 8.05 (1H, d, J = 7.7 Hz), 7.38 (1H, d, J = 7.7 Hz), 7.24 (1H,t, J = 7.3 Hz), 7.17 (1H, t, J = 7.7 Hz), 4.89 (1H, dd, J = 7.1, 3.8Hz), 4.61 (1H, t, J = 4.8 Hz), 4.31 (1H, d, J = 9.1 Hz), 4.11-4.22 (2H,m), 3.42 (2H, d, J = 5.1 Hz), 3.31 (1 H, s), 3.21 (2H, dd, J = 13.0, 6.4Hz), 3.13 (1H, ddd, J = 12.3, 6.4, 6.2 Hz), 2.34 (1H, dd, J = 12.8, 7.0Hz), 1.97- 2.07 (1H, m), 0.98 (9H, s) 433.2 355

1H NMR (400 MHz, DMSO-d6) δ ppm 9.18 (1H, d, J = 9.1 Hz), 8.18 (1H, t, J= 5.3 Hz), 7.81 (1H, dd, J = 9.5, 2.6 Hz), 7.39 (1H, dd, J = 8.8, 4.4Hz), 7.09 (1H, td, J = 9.1, 2.6 Hz), 4.39 (1H, t, J = 5.1 Hz), 4.25 (1H,d, J = 9.1 Hz), 3.81 (3H, dd, J = 11.2, 7.1 Hz), 3.77 (1H, br. s.), 3.42(1H, d, J = 5.5 Hz), 3.39 (1H, d, J = 4.8 Hz), 3.19 (1H, br. s.), 3.22(2H, d, J = 11.0 Hz), 3.01-3.14 (1H, m), 2.06 (1 H, dd, J = 7.3, 4.0Hz), 1.58 (1H, dd, J = 6.6, 2.6 Hz), 1.53 (2H, d, J = 15.4 Hz), 1.32H,d, J = 12.1 Hz), 1.31 (1H, q, J = 11.5 Hz), 0.92-1.00 (9H, m) 464.2 356

1H NMR (400 MHz, DMSO-d6) δ ppm 9.18 (1H, d, J = 8.8 Hz), 8.20 (1H, t, J= 5.9 Hz), 7.81 (1H, dd, J = 9.7, 2.4 Hz), 7.39 (1H, dd, J = 8.6, 4.6Hz), 4.61 (1H, t, J = 5.3 Hz), 4.29 (1H, d, J = 8.8 Hz), 3.81 (3H, dd, J= 11.2, 7.1 Hz), 3.77 (1H, br. s.), 3.42 (1H, d, J = 5.9 Hz), 3.38- 3.46(1H, m), 3.19 (1H, d, J = 5.9 Hz), 3.23 (2H, d, J = 9.5 Hz), 3.12 (1H,t, J = 12.6 Hz), 2.06 (1H, ddd, J = 7.2, 4.0, 3.8 Hz), 1.46 (1H, d, J =13.5 Hz), 1.53 (2H, d, J = 11.7 Hz), 1.32 (1H, d, J = 8.1 Hz), 1.26-1.37(1H, m), 0.92-1.00 (10 H, m) 450.2 357

1H NMR (400 MHz, DMSO-d6) δ ppm 9.15 (1H, d, J = 9.1 Hz), 8.06 (1H, d, J= 7.3 Hz), 7.63 (1H, br. s.), 7.33 (1H, t, J = 7.1 Hz), 7.37 (1H, d, J =7.3 Hz), 7.19 (2H, s), 7.24 (1H, d, J = 9.5 Hz), 7.16 (3 H, d, J = 10.6Hz), 5.18 (2H, s), 4.27 (1 H, d, J = 8.8 Hz), 1.00 (9H, s) 399.0 (M + H)358

1H NMR (400 MHz, DMSO-d6) δ ppm 9.17 (2H, d, J = 8.8 Hz), 8.02 (1H, d, J= 7.3 Hz), 7.61 (1H, br. s.), 7.31 (2H, d, J = 8.1 Hz), 7.20-7.27 (1H,m), 7.13 (2 H, d, J = 6.6 Hz), 7.06-7.20 (1H, m), 6.88 (2H, d, J = 8.1Hz), 5.03 (2H, d, J = 5.1 Hz), 4.24 (1H, d, J = 8.8 Hz), 3.69 (3H, s),0.99 (8H, s) 411.0 (M + H) 359

1H NMR (400 MHz, DMSO-d6) δ ppm 9.42 (1H, d, J = 8.8 Hz), 8.03 (1H, d, J= 7.0 Hz), 7.29-7.39 (4H, m), 7.14- 7.24 (3H, m), 7.02 (2H, s), 5.14(2H, s), 4.89 (1H, d, J = 8.8 Hz), 1.04 (9H, s) 420.2 360

1H NMR (400 MHz, DMSO-d6) δ ppm 10.90 (1H, br. s.), 8.18 (1H, br. s.),7.24- 7.34 (4H, m), 6.99 (1H, d, J = 2.9 Hz), 6.94 (1H, d, J = 4.8 Hz),6.96 (1H, d, J = 5.9 Hz), 4.99 (2H, s), 4.69 (1H, t, J = 4.8 Hz), 3.71(1H, s), 3.36-3.47 (4 H, m), 0.99 (1H, s), 0.93 (10H, s) 424.2 361

1H NMR (400 MHz, DMSO-d6) δ ppm 9.21 (1H, d, J = 8.8 Hz), 8.18 (1H, t, J= 5.5 Hz), 8.05 (1H, d, J = 7.0 Hz), 7.28- 7.39 (4H, m), 7.21-7.25 (1H,m), 7.17 (2H, dd, J = 14.8, 7.5 Hz), 5.13 (2H, d, J = 2.6 Hz), 4.41 (1H,d, J = 8.8 Hz), 4.36- 4.44 (1H, m), 4.27 (1H, d, J = 8.8 Hz), 3.42 (1H,d, J = 5.5 Hz), 3.32-3.41 (1H, m), 3.17-3.27 (2H, m), 3.08 (1H, dt, J =12.8, 6.4 Hz), 1.54-1.64 (2H, m), 0.99 (8H, s) 438.2 362

1H NMR (400 MHz, DMSO-d6) δ ppm 9.18 (1H, d, J = 9.2 Hz), 8.06 (1H, d, J= 8.8 Hz), 7.61-7.75 (1H, m), 7.35- 7.48 (1H, m), 7.05-7.30 (5H, m),5.08- 5.22 (2H, in), 4.26 (1H, d, J = 9.2 Hz), 1.00 (8H, s) 399.3 (M +H) 363

1H NMR (400 MHz, DMSO-d6) δ ppm 9.18 (1H, d, J = 9.2 Hz), 8.05 (1H, d, J= 7.7 Hz), 7.65-7.71 (1H, m), 7.44 (2 H, dd, J = 8.8, 5.5 Hz), 7.09-7.29(5H, m), 5.04-5.19 (2H, m), 4.26 (1H, d, J = 8.8 Hz), 1.00 (9H, s) 399.3(M + H) 364

1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 (s, 9H) 1.24-1.35 (m, 2H) 1.52-1.59 (m, 2H) 2.10-2.20 (m, 1H) 3.18- 3.26 (m, 3H) 3.84 (br. s., 1H) 3.81(d, J = 6.22 Hz, 3H) 4.25 (d, J = 8.78 Hz, 1H) 7.13-7.21 (m, 1H) 7.63(br. s., 1H) 8.15 (d, J = 5.12 Hz, 1H) 8.19 (d, J = 8.05 Hz, 1H) 8.99(d, J = 8.78 Hz, 1H) 389.2 365

1H NMR (400 MHz, DMSQ-d6) δ ppm 9.00 (1H, d, J = 9.1 Hz), 8.26 (1H, d, J= 9.1 Hz), 8.18 (1H, d, J = 8.1 Hz), 8.15 (1H, d, J = 4.4 Hz), 7.63 (1H,br. s.), 7.43 (1H, d, J = 9.1 Hz), 7.18 (1H, d, J = 2.2 Hz), 7.16 (1H,br. s.), 4.25 (1H, d, J = 8.8 Hz), 3.91 (1H, t, J = 7.1 Hz), 3.34-3.45(1H, m), 1.76 (1H, t), 1.27-1.37 (3H, m), 1.18-1.23 (2H, m), 1.12-1.18(2 H, m), 1.00 (7H, s), 0.86 (2H, t, J = 6.8 Hz) 361.2 366

1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (s, 1H) 1.01 (s, 9H) 4.27 (d, J =8.78 Hz, 1H) 5.13 (d, J = 4.76 Hz, 2H) 7.17 (d, J = 6.95 Hz, 1H) 7.15(d, J = 5.49 Hz, 2H) 7.21 (s, 1H) 7.29-7.39 (m, 4 H) 7.63 (br. s., 1H)8.06 (d, J = 7.32 Hz, 1 H) 9.19 (d, J = 8.78 Hz, 1H) 380.2 367

1H NMR (400 MHz, DMSQ-d6) δ ppm 9.15 (1H, d, J = 9.1 Hz), 8.06 (1H, d, J= 7.3 Hz), 7.63 (1H, br. s.), 7.33 (1H, t, J = 7.1 Hz), 7.37 (1H, d, J =7.3 Hz), 7.19 (2H, s), 7.24 (1H, d, J = 9.5 Hz), 7.16 (3 H, d, J = 10.6Hz), 5.18 (2H, s), 4.27 (1 H, d, J = 8.8 Hz), 1.00 (9H, s) 399 (M + H)368

1H NMR (400 MHz, DMSO-d6) δ ppm 9.17 (2H, d, J = 8.8 Hz), 8.02 (1H, d, J= 7.3 Hz), 7.61 (1H, br. s.), 7.31 (2H, d, J = 8.1 Hz), 7.20-7.27 (1H,m), 7.13 (2 H, d, J = 6.6 Hz), 7.06-7.20 (1H, m), 6.88 (2H, d, J = 8.1Hz), 5.03 (2H, d, J = 5.1 Hz), 4.24 (1H, d, J = 8.8 Hz), 3.69 (3H, s),0.99 (8H, s) 411 (M + H) 369

1H NMR (400 MHz, DMSO-d6) δ ppm 1.04 (s, 9H) 4.89 (d, J = 8.78 Hz, 1H)5.14 (s, 2H) 7.02 (s, 2H) 7.14-7.24 (m, 3H) 7.29-7.39 (m, 4H) 8.03 (d, J= 6.95 Hz, 1H) 9.42 (d, J = 8.78 Hz, 1H) 420.2 370

1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (s, 10H) 0.99 (s, 1H) 3.36-3.47 (m,4H) 3.71 (s, 1H) 4.69 (t, J = 4.76 Hz, 1H) 4.99 (s, 2H) 6.96 (d, J =5.86 Hz, 1 H) 6.94 (d, J = 4.76 Hz, 1H) 6.99 (d, J = 2.93 Hz, 1H)7.24-7.34 (m, 4H) 8.18 (br. s., 1H) 10.90 (br. s., 1H) 424.2 371

1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (s, 2H) 0.99 (s, 8H) 1.53-1.65 (m,2H) 3.08 (dt, J = 12.81, 6.40 Hz, 1H) 3.16-3.27 (m, 2H) 3.32-3.41 (m,1H) 3.42 (d, J = 5.49 Hz, 1H) 4.27 (d, J = 8.78 Hz, 1H) 4.36-4.44 (m,1H) 5.13 (d, J = 2.56 Hz, 2H) 7.17 (dd, J = 14.82, 7.50 Hz, 2H)7.21-7.25 (m, 1H) 7.28-7.39 (m, 4H) 8.05 (d, J = 6.95 Hz, 1H) 8,18 (t, J= 5.49 Hz, 1H) 9.21 (d, J = 8.78 Hz, 1H) 438.2 372

1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 (s, 8H) 4.26 (d, J = 8.79 Hz, 1H)5.24 (s, 2H) 7.13-7.25 (m, 3H) 7.55 (d, J = 8.42 Hz, 2H) 7.64-7.71 (m,1H) 7.83 (d, J = 8.05 Hz, 1H) 9.15 (d, J = 8.79 Hz, 1H) 406 (M + H) 373

1H NMR (400 MHz, DMSO-d6) δ ppm 0.99 (s, 8H) 4.27 (d, J = 9.15 Hz, 1H)5.34 (d, J = 3.29 Hz, 2H) 7.10-7.21 (m, 3H) 7.23 (d, J = 1.83 Hz, 1H)7.34 (d, J = 8.05 Hz, 1H) 7.52 (t, J = 7.50 Hz, 1H) 7.62-7.70 (m, 2H)9.13 (d, J = 9.15 Hz, 1H) 406 (M + H) 374

1H NMR (400 MHz, DMSO-d6) δ ppm 9.18 (1H, d, J = 9.2 Hz), 8.06 (1H, d, J= 8.8 Hz), 7.61-7.75 (1H, m), 7.35- 7.48 (1H, m), 7.05-7.30 (5H, m),5.08- 5.22 (2H, m), 4.26 (1H, d, J = 9.2 Hz), 1.00 (8H, s) 399 (M + H)375

1H NMR (400 MHz, DMSO-d6) δ ppm 9.18 (1H, d, J = 9.2 Hz), 8.05 (1H, d, J= 7.7 Hz), 7.65-7.71 (1H, m), 7.44 (2 H, dd, J = 8.8, 5.5 Hz), 7.09-7.29(5H, m), 5.04-5.19 (2H, m), 4.26 (1H, d, J = 8.8 Hz), 1.00 (9H, s) 399(M + H) 376

1H NMR (400 MHz, DMSO-d6) δ ppm 0.98 (s, 9H) 3.07-3.16 (m, 1H) 3.07-3.26 (m, 2H) 3.41 (d, J = 5.86 Hz, 2H) 3.41 (d, J = 17.57 Hz, 2H) 4.31(d, J = 9.15 Hz, 1H) 4.67 (d, J = 10.62 Hz, 1 H) 4.67 (s, 1H) 5.06-5.18(m, 2H) 7.12- 7.22 (m, 4H) 7.23-7.28 (m, 1H) 7.25 (s, 1H) 7.44 (dd, J =8.79, 5.49 Hz, 2H) 8.05 (s, 1H) 8.03 (s, 1H) 8.26 (s, 1H) 8.26 (d, J =11.35 Hz, 1H) 9.21 (d, J = 9.15 Hz, 1H) 443 (M + H) 377

1H NMR (400 DMSO-d6) δ ppm 0.98 (s, 8H) 1.51-1.62 (m, J = 9.65, 6.77,6.61, 6.61 Hz, 2H) 3.00-3.10 (m, 1H) 3.19 (dt, J = 13.18, 6.59 Hz, 1H)3.38-3.45 (m, 2H) 4.27 (d, J = 8.79 Hz, 1H) 4.44 (t, J = 5.12 Hz, 1H)5.07-5.17 (m, 2H) 7.10-7.28 (m, 4H) 7.44 (dd, J = 8.79, 5.49 Hz, 2H)8.23 (t, J = 5.49 Hz, 1H) 9.21 (d, J = 9.15 Hz, 1H) 457 (M + H) 378

1H NMR (400 MHz, DMSO-d6) δ ppm 1.01 (s, 9H) 3.68 (dd, J = 5.67, 4.21Hz, 2H) 4.34 (d, J = 8.42 Hz, 1H) 5.12 (dd, J = 2.93, 0.73 Hz, 2H) 7.03(d, J = 0.73 Hz, 1H) 7.12-7.22 (m, 4H) 7.24-7.30 (m, 2H) 7.44 (dd, J =8.79, 5.49 Hz, 2H) 8.01-8.06 (m, 1H) 8.46 (d, J = 11.71 Hz, 1H) 8.46 (s,1H) 9.23 (d, J = 8.42 Hz, 1 H) 456 (M + H) 379

1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (s, 9H) 4.89 (d, J = 8.79 Hz, 1H)5.13 (s, 2H) 7.09 (s, 2H) 7.18 (t, J = 8.97 Hz, 4H) 7.24 (s, 1H) 7.45(dd, J = 8.79, 5.49 Hz, 2H) 8.01 (s, 1H) 9.42 (d J = 8.79 Hz, 1H) 439(M + H)

Although the invention has been described above with reference to thedisclosed embodiments, those skilled in the art will readily appreciatethat the specific experiments detailed are only illustrative of theinvention. It should be understood that various modifications can bemade without departing from the spirit of the invention.

1. A method for the treatment of a condition mediated by CB1 receptoractivity in a mammalian subject including a human, which comprisesadministering to a mammal in need of such treatment a therapeuticallyeffective amount of the compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: A is a carbonatom or a nitrogen atom; B is a carbon atom or a nitrogen atom; R¹ is aC₁-C₄ alkyl group substituted with 1 to 3 substituents independentlyselected from the group consisting of a halo group, a C₁-C₄ alkyl group;a hydroxy group; a C₁-C₄ alkoxy group; a mercapt group; a C₁-C₄alkylthio group; a C₁-C₄ alkylsulfinyl group; a C₁-C₄ alkylsulfonylgroup; an amino group; a C₁-C₄ alkylamino group; a di(C₁-C₄ alkyl)aminogroup; a (C₁-C₄ alkyl)(C₁-C₄ alkylsulfonyl)amino group; a cycloalkylgroup; a cycloalkyl group substituted with 1 to 3 substituents selectedfrom the group consisting of a hydroxy group, a C₁-C₄ alkoxy group and aC₁-C₄ alkyl group; a heterocyclyl group; a heterocyclyl groupsubstituted with 1 to 3 substituents selected from the group consistingof a hydroxy group, a C₁-C₄ alkoxy group, a C₁-C₄ alkyl group and an oxogroup; a cyano group; a heteroaryl group and a C₁-C₄ alkyl heteroarylgroup; R² is a cycloalkyl group; a cycloalkyl group substituted with 1to 4 substituents selected from the group consisting of a hydroxy group,a C₁-C₄ hydroxyalkyl group, a C₁-C₄ alkoxy group, a C₆-C₁₀ aryloxygroup, a mercapt group, a C₁-C₄ alkylthio group, a C₆-C₁₀ arylthiogroup, a carboxy group, a C₁-C₄ alkoxy-carbonyl group, a C₁-C₄ alkylgroup, a C₂-C₄ alkenyl group, a C₂-C₄ alkynyl group and anamino-carbonyl group; a C₆-C₁₀ aryl group; a C₆-C₁₀ aryl groupsubstituted with 1 to 3 substituents selected from the group consistingof a hydroxy group and a C₁-C₄ alkyl group; a heterocyclyl group; aheterocyclyl group substituted with 1 to 3 substituents selected fromthe group consisting of a hydroxy group and a C₁-C₄ alkyl group; aC₁-C₁₀ alkyl group; or a C₁-C₁₀ alkyl group substituted with 1 to 3substituents independently selected from the group consisting of a cyanogroup, a hydroxy group, a trifluoromethyl group, a C₂-C₄ alkenyl group,a C₂-C₄ alkynyl group, a C₁-C₄ alkoxy group, a C₆-C₁₀ aryloxy group, amercapt group, a C₁-C₄ alkylthio group, a C₁-C₄ alkylsulfinyl group, aC₁-C₄ alkylsulfonyl group, a C₁-C₄ alkylsulfonylamino group, a C₆-C₁₀arylthio group, a carboxy group, a C₁-C₄alkyl-carbonyl group, atrifluoromethyl-carbonyl group, a C₁-C₄ alkoxy-carbonyl group, an aminocarbonyl group, a C₁-C₄ alkylamino-carbonyl group, a C₁-C₄hydroxyalkylamino-carbonyl group, a di(C₁-C₄ alkyl)amino-carbonyl group,a (C₁-C₄ hydroxyalkyl)(C₁-C₄ alkyl)amino-carbonyl group, aheterocyclyl-carbonyl group, a cycloalkyl group, a heterocyclyl group, aC₁-C₄ alkyl-substituted heterocyclyl group, a C₆-C₁₀ aryl group, adi(C₁-C₄ alkyl)amino group, a C₁-C₄ alkoxy C₁-C₄ alkylamino-carbonylgroup, an aryl C₁-C₄alkylamino-carbonyl group, and a heteroaryl C₁-C₄alkylamino-carbonyl group and R³ is a hydrogen atom, a halogen atom, ahydroxy group, a C₁-C₄ alkyl group, a C₁-C₄ haloalkyl group, a C₁-C₄alkoxy group, a C₁-C₄ alkylthio group, a C₁-C₄ alkylsulfonyl group, aC₁-C₄ alkylsulfinyl group or an aminosulfonyl group.
 2. The method ofclaim 1, wherein: A is a carbon atom or a nitrogen atom; B is a carbonatom or a nitrogen atom; R¹ is a C₁-C₄ alkyl group substituted with 1 to3 substituents independently selected from the group consisting of aC₁-C₄ alkyl group; a hydroxy group; a C₁-C₄ alkoxy group; a mercaptgroup; a C₁-C₄ alkylthio group; a C₁-C₄ alkylsulfinyl group; a C₁-C₄alkylsulfonyl group; an amino group; a C₁-C₄ alkylamino group; adi(C₁-C₄ alkyl)amino group; a (C₁-C₄ alkyl)(C₁-C₄ alkylsulfonyl)aminogroup; a cycloalkyl group; a cycloalkyl group substituted with 1 to 3substituents selected from the group consisting of a hydroxy group, aC₁-C₄ alkoxy group and a C₁-C₄ alkyl group; a heterocyclyl group; and aheterocyclyl group substituted with 1 to 3 substituents selected fromthe group consisting of a hydroxy group, a C₁-C₄ alkoxy group and aC₁-C₄ alkyl group; R² is a cycloalkyl group; a cycloalkyl groupsubstituted with 1 to 4 substituents selected from the group consistingof a hydroxy group, a C₁-C₄ hydroxyalkyl group, a C₁-C₄ alkoxy group, aC₆-C₁₀ aryloxy group, a mercapt group, a C₁-C₄ alkylthio group, a C₆-C₁₀arylthio group, a carboxy group, a C₁-C₄ alkoxy-carbonyl group, a C₁-C₄alkyl group, a C₂-C₄ alkenyl group and a C₂-C₄ alkynyl group; a C₆-C₁₀aryl group; a C₆-C₁₀ aryl group substituted with 1 to 3 substituentsselected from the group consisting of a hydroxy group and a C₁-C₄ alkylgroup; a heterocyclyl group; a heterocyclyl group substituted with 1 to3 substituents selected from the group consisting of a hydroxy group anda C₁-C₄ alkyl group; a C₁-C₁₀ alkyl group; or a C₁-C₁₀ alkyl groupsubstituted with 1 to 3 substituents independently selected from thegroup consisting of a cyano group, a hydroxy group, a trifluoromethylgroup, a C₂-C₄ alkenyl group, a C₂-C₄ alkynyl group, a C₁-C₄ alkoxygroup, a C₆-C₁₀ aryloxy group, a mercapt group, a C₁-C₄ alkylthio group,a C₁-C₄ alkylsulfinyl group, a C₁-C₄ alkylsulfonyl group, a C₁-C₄alkylsulfonylamino group, a C₆-C₁₀ arylthio group, a carboxy group, aC₁-C₄ alkyl-carbonyl group, a trifluoromethyl-carbonyl group, a C₁-C₄alkoxy-carbonyl group, an amino carbonyl group, a C₁-C₄alkylamino-carbonyl group, a C₁-C₄ hydroxyalkylamino-carbonyl group, adi(C₁-C₄ alkyl)amino-carbonyl group, a (C₁-C₄ hydroxyalkyl)(C₁-C₄alkyl)amino-carbonyl group, a heterocyclyl-carbonyl group, a cycloalkylgroup, a heterocyclyl group, a C₁-C₄ alkyl-substituted heterocyclylgroup and a C₆-C₁₀ aryl group; and R³ is a hydrogen atom, a halogenatom, a hydroxy group, a C₁-C₄ alkyl group, C₁-C₄ haloalkyl group or aC₁-C₄ alkoxy group.
 3. The method of claim 1, wherein: A is a carbonatom or a nitrogen atom; B is a carbon atom or a nitrogen atom; R¹ is aC₁-C₄ alkyl group substituted with 1 to 3 substituents independentlyselected from the group consisting of a halo group, a C₁-C₄ alkyl group;a C₁-C₄ alkylthio group; a cyano group; a heteroaryl group, a C₁-C₄alkyl heteroaryl group; a cycloalkyl group; a cycloalkyl groupsubstituted with hydroxy group, a heterocyclyl group; and a heterocyclylgroup substituted with an oxo group; R² is a cycloalkyl groupsubstituted with a hydroxy group or an amino carbonyl group; a C₆-C₁₀aryl group substituted with a hydroxy group; or a C₁-C₁₀ alkyl groupsubstituted with 1 to 3 substituents independently selected from thegroup consisting of a hydroxy group, an amino carbonyl group, a di(C₁-C₄alkyl)amino group, a cycloalkyl group, a heterocyclyl group, a C₁-C₄alkyl-substituted heterocyclyl group, a C₆-C₁₀ aryl group, a C₁-C₄alkoxy C₁-C₄ alkylamino-carbonyl group, an aryl C₁-C₄alkylamino-carbonylgroup, and a heteroaryl C₁-C₄alkylamino-carbonyl group; R³ is a hydrogenatom, a halogen atom, a hydroxy group, a C₁-C₄ alkyl group, a C₁-C₄haloalkyl group, a C₁-C₄ alkoxy group, a C₁-C₄ alkylthio group, a C₁-C₄alkylsulfonyl group, a C₁-C₄ alkylsulfinyl group or an aminosulfonylgroup.
 4. The method of claim 3 wherein A is a carbon atom and B is acarbon atom.
 5. The method of claim 1, wherein said condition isselected from the group consisting of inflammatory pain, nociceptivepain, neuropathic pain, fibromyalgia, chronic low back pain, visceralpain, acute cerebral ischemia, pain, chronic pain, acute pain, postherpetic neuralgia, neuropathies, neuralgia, diabetic neuropathy,HIV-related neuropathy, nerve injury, rheumatoid arthritic pain,osteoarthritic pain, back pain, cancer pain, dental pain, fibromyalgia,neuritis, sciatica, inflammation, neurodegenerative disease, spasticity,epilepsy, Tourette's syndrome, Parkinson's disease, neuroprotection,anxiety, cough, broncho constriction, irritable bowel syndrome (IBS),Inflammatory bowel disease (IBD), colitis, cerebrovascular ischemia,cachexia, nausea, emesis, chemotherapy-induced emesis, rheumatoidarthritis, asthma, Crohn's disease, ulcerative colitis, asthma,dermatitis, seasonal allergic rhinitis, gastroesophageal reflux disease(GERD), constipation, diarrhea, functional gastrointestinal disorder,cutaneous T cell lymphoma, multiple sclerosis, osteoarthritis,psoriasis, systemic lupus erythematosus, diabetes, glaucoma,osteoporosis, glomerulonephritis, renal ischemia, nephritis, hepatitis,cerebral stroke, vasodilation, hypertension, vasculitis, myocardialinfarction, cerebral ischemia, reversible airway obstruction, adultrespiratory disease syndrome, chronic obstructive pulmonary disease(COPD), cryptogenic fibrosing alveolitis and bronchitis.
 6. A compoundof formula (I):

or a pharmaceutically acceptable salt thereof, wherein: A is a carbonatom or a nitrogen atom; B is a carbon atom or a nitrogen atom; R¹ isselected from the group consisting of H, CH₃—(CH₂)₄—, cyano-(CH₂)₃—,cyano-(CH₂)₄—, CF₃—(CH₂)₂—, cyclobutyl-CH₂—, cyclobutyl-(CH₂)₂—,cyclopropyl-(CH₂)₃—, cyclohexyl-CH₂—, OH-cyclohexyl-CH₂—,tetrahydrofuranyl-CH₂—, tetrahydropyranyl-CH₂—,oxo-tetrahydrofuranyl-CH₂—, oxo-pyrrolidinyl-CH₂—, pyridinyl-CH₂—,pyrazinyl-CH₂—, pyrimidinyl-CH₂—, CH₃-pyrazolyl-CH₂—, CH₃-oxazolyl-CH₂—,CH₃-isoxazolyl-CH₂—, CH₃-oxadiazolyl-CH₂—, CH₃-thiazolyl-CH₂—, andCH₃-thiadiazolyl-CH₂—; R² is selected from the group consisting of H,NR⁴R⁵—C(O)—CR⁶R⁷—, CR⁸R⁹R¹⁰—, (CH₃)₂—N—CH₂—C(CH₃)₂—CH₂—,tetrahydronaphthalenyl, OH-dihydroindenyl, OH-cyclohexyl, andCH₃—CH₂-pyrrolidinyl-CH₂—; R³ is selected from the group consisting ofH, F, Cl, methyl, cyano, methoxy, trifluoromethyl, methylthio,methylsulfinyl, methylsulfonyl and aminosulfonyl; R⁴ and R⁵ are H,OH—(CH₂)₂—, NH₂—C(O)—(CH₂)₂—, CH₃—O—(CH₂)₂—, benzyl, or pyridinyl; R⁶and R⁷ are H, (CH₃)₃—C—, CH₃, benzyl, phenyl, tetrahydropyranyl, orcyclohexyl; R⁸, R⁹ and R¹⁰ are H, (CH₃)₃—C—, NH₂—C(O), OH—CH₂—,(CH₃CH₂)₂—N—CH₂—, or CH₃; or two of R⁸, R⁹, or R¹⁰ form a cyclohexyl. 7.The compound of claim 6 or a pharmaceutically acceptable salt thereof,wherein: A is a carbon atom; B is a carbon atom; R¹ is selected from thegroup consisting of H, CH₃—(CH₂)₄—, cyano-(CH₂)₃—, cyano-(CH₂)₄—,CF₃—(CH₂)₂—, cyclobutyl-CH₂—, cyclobutyl-(CH₂)₂—, cyclopropyl-(CH₂)₃—,cyclohexyl-CH₂—, OH-cyclohexyl-CH₂—, tetrahydrofuranyl-CH₂—,tetrahydropyranyl-CH₂—, oxo-tetrahydrofuranyl-CH₂—,oxo-pyrrolidinyl-CH₂, pyridinyl-CH₂—, pyrazinyl-CH₂—, pyrimidinyl-CH₂—,CH₃-pyrazolyl-CH₂—, CH₃-oxazolyl-CH₂—, CH₃-isoxazolyl-CH₂—,CH₃-oxadiazolyl-CH₂—, CH₃-thiazolyl-CH₂—, and CH₃-thiadiazolyl-CH₂—; R²is selected from the group consisting of H, NR⁴R⁵—C(O)—CR⁶R⁷—,CR⁸R⁹R¹⁰—, (CH₃)₂—N—CH₂—C(CH₃)₂—CH₂—, tetrahydronaphthalenyl,OH-dihydroindenyl, OH-cyclohexyl, and CH₃—CH₂-pyrrolidinyl-CH₂—; R³ isselected from the group consisting of H, F, Cl, methyl, cyano, methoxy,trifluoromethyl, methylthio, methylsulfinyl, methylsulfonyl andaminosulfonyl; R⁴ and R⁵ are H, OH—(CH₂)₂—, NH₂—C(O)—(CH₂)₂—,CH₃—O—(CH₂)₂—, benzyl, or pyridinyl; R⁶ and R⁷ are H, (CH₃)₃—C—, CH₃,benzyl, phenyl, tetrahydropyranyl, or cyclohexyl; R⁸, R⁹ and R¹⁰ are H,(CH₃)₃—C—, NH₂—C(O)—, OH—CH₂—, (CH₃CH₂)₂—N—CH₂—, or CH₃; or two of R⁸,R⁹, or R¹⁰ form a cyclohexyl.
 8. The compound of claim 7 or apharmaceutically acceptable salt thereof, wherein R¹ is selected fromthe group consisting of


9. The compound of claim 7 or a pharmaceutically acceptable saltthereof, wherein R² is selected from the group consisting of


10. A method of treatment comprises administering to a mammal in need ofsuch treatment a therapeutically effective amount of the compoundN-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamideorN-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-4-methyl-3-[2-(methylthio)ethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamideor a pharmaceutically acceptable salt thereof.
 11. The compound of claim7 selected from the group consisting ofN-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclohexylmethyl)fluoro-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-6-chloro-3-cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclohexylmethyl)-6-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-6-cyano-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-cyclohexylmethyl)-5-fluoro-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-5-chloro-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-5-cyano-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclohexylmethyl)-4-fluoro-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-4-chloro-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclohexylmethyl)-4-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-4-cyano-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;3-(cyclohexylmethyl)-N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1carboxamide;3-(cyclobutylmethyl)-N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]-2-oxo-3-pentyl-2,3-dihydro-1H-benzimidazole-1-carboxamide;3-(cyclohexylmethyl)-N-{[(2S)-1-ethylpyrrolidin-2-yl]methyl}-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;3-(cyclobutylmethyl)-N-{[(2S)-1-ethylpyrrolidin-2-yl]methyl}-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-{[(2S)-1-ethylpyrrolidin-2-yl]methyl}-2-oxo-3-pentyl-2,3-dihydro-1H-benzimidazole-1-carboxamide;3-(cyclohexylmethyl)-N-[3-(dimethylamino)-2,2-dimethylpropyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;3-(cyclobutylmethyl)-N-[3-(dimethylamino)-2,2-dimethylpropyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[3-(dimethylamino)-2,2-dimethylpropyl]-2-oxo-3-pentyl-2,3-dihydro-1H-benzimidazole-1-carboxamide;3-(cyclohexylmethyl)-N-[2-(diethylamino)-1-methylethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;3-(cyclobutylmethyl)-N-[2-diethylamino)-1-methylethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[2-(diethylamino)-1-methylethyl]-2-oxo-3-pentyl-2,3-dihydro-1H-benzimidazole-1-carboxamide;3-(cyclohexylmethyl)-N-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;3-(cyclobutylmethyl)-N-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-2-oxo-3-pentyl-2,3-dihydro-1H-benzimidazole-1-carboxamide;3-(cyclohexylmethyl)-N-[(1S,2S-2-hydroxycyclohexyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;3-(cyclobutylmethyl)-N-[(1S,2S)-2-hydroxycyclohexyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S,2S)-2-hydroxycyclohexyl]-2-oxo-3-pentyl-2,3-dihydro-1H-benzimidazole-1-carboxamide;3-(cyclohexylmethyl)-N-(trans-4-hydroxycyclohexyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;3-(cyclobutylmethyl)-N-(trans-4-hydroxycyclohexyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-(trans-4-hydroxycyclohexyl)-2-oxo-3-pentyl-2,3-dihydro-1H-benzimidazole-1-carboxamide;3-(cyclohexylmethyl)-2-oxo-N-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-2,3-dihydro-1H-benzimidazole-1-carboxamide;3-(cyclobutylmethyl)-2-oxo-N-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-2,3-dihydro-1H-benzimidazole-1-carboxamide;2-oxo-3-pentyl-N-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclobutylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-pentyl-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-3-(cyclobutylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-2-oxo-3-pentyl-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-(cyclobutylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-(2-amino-1,1-dimethyl-2-oxoethyl)-2-oxo-3-pentyl-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[1-(aminocarbonyl)cyclohexyl]-3-cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[1-(aminocarbonyl)cyclohexyl]-3-(cyclobutylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[1-(aminocarbonyl)cyclohexyl]-2-oxo-3-pentyl-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-2-amino-2-oxo-1-phenylethyl]-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-2-amino-2-oxo-1-phenylethyl]-3-(cyclobutylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-2-amino-2-oxo-1-phenylethyl]-2-oxo-3-pentyl-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-alpha-{[3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}-L-phenylalaninamide;N-alpha-{[3-(cyclobutylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}-L-phenylalaninamide;N-alpha-[(2-oxo-3-pentyl-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]-L-phenylalaninamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(2-cyclobutylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(3-cyclopropylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-(pyridin-2-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-(pyridin-2-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-(pyrimidin-2-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-(aminocarbonyl-2,2-dimethylpropyl]-2-oxo-3-(pyridazin-3-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-(pyrimidin-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[(5-methylisoxazol-3-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[(5-methyl-1H-pyrazol-3-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[(1-methyl-1H-pyrazol-3-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-aminocarbonyl)-2,2-dimethylpropyl]-3-[(2-methyl-1,3-oxazol-5-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[(2-methyl-1,3-thiazol-5-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(3-cyanopropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(4-cyanobutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-2-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-(tetrahydrofuran-2-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-(2-cyclobutylethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-(3-cyanopropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-2-amino-2-oxo-1-phenylethyl]-2-oxo-3-(pyridin-2-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-2-amino-2-oxo-1-phenylethyl]-2-oxo-3-(pyrazin-2-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-2-amino-2-oxo-1-phenylethyl]-3-[(5-methylisoxazol-3-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-alpha-({3-[(1-methyl-1H-pyrazol-3-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}-carbonyl)-L-phenylalaninamide;N-alpha-({3-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}-carbonyl)-L-phenylalaninamide;N-alpha-({2-oxo-3-[(5-oxotetrahydrofuran-2-yl)methyl]-2,3-dihydro-1H-benzimidazol-1-yl}carbonyl)-L-phenylalaninamide;N-alpha-({2-oxo-3-[(5-oxopyrrolidin-2-yl)methyl]-2,3-dihydro-1H-benzimidazol-1-yl}carbonyl)-L-phenylalaninamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclohexylmethyl)-4-methoxy-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3(cyclohexylmethyl)-5-methoxy-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclohexylmethyl)-2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-carboxamide;N-[(1S)-2-amino-1cyclohexyl-2-oxoethyl]-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-2-amino-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl]-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[(1-hydroxycyclohexyl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;3-(cyclohexylmethyl)-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;3-(cyclohexylmethyl)-N-[(1S)-1-{[(2-methoxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-{(1S)-1-[(benzylamino)carbonyl]-2,2-dimethylpropyl}-3(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;3-(cyclohexylmethyl)-N-[(1S)-2,2-dimethyl-1-{[(pyridin-2-ylmethyl)amino]carbonyl}propyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-{[3(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}-3-methyl-L-valyl-beta-alaninamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclohexylmethyl)-5-(methylthio-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3(cyclohexylmethyl)-5(methylsulfinyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3(cyclohexylmethyl)-5-(methylsulfonyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-5-(aminosulfonyl)-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;andN-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-(3,3,3-trifluoropropyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide.12. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: A is a carbonatom or a nitrogen atom; B is a carbon atom or a nitrogen atom; R¹ isselected from the group consisting of H, CH₃—(CH₂)₄—, CH₃—(CH₂)₃—,cyano-(CH₂)₃—, cyano-(CH₂)₄—, CF₃—(CH₂)₂—, cyclobutyl-CH₂—,cyclobutyl-(CH₂)₂—, cyclopropyl-(CH₂)₃—, cyclopropyl-C(O)CH₂—,CH₃—CH₂—NH—C(O)—CH₂—, (CH₃)₃—C—C(O)—CH₂—, cyclohexyl-CH₂—,OH-cyclohexyl-CH₂—, F₂-cyclohexyl-CH₂—, F-cyclohexenyl-CH₂—,tetrahydrofuranyl-CH₂—, tetrahydropyranyl-CH₂—, fluoro-benzyl,CH₃—O-benzyl, cyano-benzyl, methyl-benzyl, chloro-benzyl,oxo-tetrahydrofuranyl-CH₂—, oxo-pyrrolidinyl-CH₂—, pyridinyl-CH₂—,pyrazinyl-CH₂—, pyrimidinyl-CH₂—, CH₃-pyrazolyl-CH₂—, CH₃-oxazolyl-CH₂—,CH₃-isoxazolyl-CH₂—, CH₃-oxadiazolyl-CH₂—, CH₃-thiazolyl-CH₂—, andCH₃-thiadiazolyl-CH₂—; R² is selected from the group consisting of H,NR⁴R⁵—C(O)—CR⁶R⁷—, CR⁸R⁹R¹⁰—, (CH₃)₂—N—CH₂—C(CH₃)₂—CH₂—,tetrahydronaphthalenyl, OH-dihydroindenyl, OH-cyclohexyl,CH₃CH₂-pyrrolidinyl-CH₂—, oxadiazolyl-CR¹¹R¹²— optionally substitutedwith CH₃, NH₂, (CH₃)₂—N—C(O)—, CH₃—NH—C(O)—,tetrahydronaphthalenyl-NH—C(O)—, azepanyl-C(O)—,oxopyrrolidinyl-(CH₂)₃—NH—C(O)—, CH₃—O—(CH₂)₂—NH—C(O)—,OH-cyclohexyl-NH—C(O)—, OH—CH₂-piperidinyl-C(O)—, CH₃—CH₂—,(CH₃)₂—CH—(CH₂)₂—NH—C(O)—, or (CH₃)₂—CH—; isoxazolyl-CR¹¹R¹²— optionallysubstituted with CH₃; furyl-CR¹¹R¹²— optionally substituted with CH₃ orCF₃, pyrazolyl-CR¹¹R¹²— optionally substituted with CH₃, (CH₃)₂—CH—, orCH₃—CH₂—; thiazolyl-CR¹¹R¹²— optionally substituted with CH₃, CH₃—CH₂—,or CF₃; and dihydroisochromenyl-CR¹¹R¹²—; R³ is selected from the groupconsisting of H, F, Cl, bromo, difluoro, methyl, cyano, methoxy,trifluoromethyl, methylthio, methylsulfinyl, methylsulfonyl andaminosulfonyl; R⁴ and R⁵ are H, OH—(CH₂)₂—, NH₂—C(O)—(CH₂)₂—,CH₃—O—(CH₂)₂—, benzyl, pyridinyl, cyclobutyl, (CH₃)₃—C—, cyclopropyl,CH₃, OH—(CH₂)₃—, or (OH)₂—CH₂—CH—CH₂—; R⁶ and R⁷ are H, (CH₃)₃—C—, CH₃,benzyl, phenyl, tetrahydropyranyl, cyclohexyl, (CH₃)₂—CH—CH₂—,(CH₃)₂—CH—, or (OH)(CH₃)—CH—; R⁸, R⁹ and R¹⁰ are H, (CH₃)₃—C—,NH₂—C(O)—, OH—CH₂—, (CH₃CH₂)₂—N—CH₂—, CH₃, (OH) (CH₃)₂—CH—,CH₃—NH—C(O)—CH₂—, cyclopropyl-NH—C(O)—CH₂—, NH₂—C(O)—CH₂—NH—C(O)—CH₂—,or COOH—CH₂—; or two of R⁸, R⁹, or R¹⁰ form a cyclohexyl, and R¹¹ andR¹² are H, CH₃, or (CH₃)₃—C—.
 13. The compound of claim 12 or apharmaceutically acceptable salt thereof, wherein: A is a carbon atom; Bis a carbon atom; R¹ is selected from the group consisting of H,CH₃—(CH₂)₄—, CH₃—(CH₂)₃—, cyano-(CH₂)₃—, cyano-(CH₂)₄—, CF₃—(CH₂)₂—,cyclobutyl-CH₂—, cyclobutyl-(CH₂)₂—, cyclopropyl-(CH₂)₃—,cyclopropyl-C(O)CH₂—, CH₃—CH₂—NH—C(O)—CH₂—, (CH₃)₃—C—C(O)—CH₂—,cyclohexyl-CH₂—, OH-cyclohexyl-CH₂—, F₂-cyclohexyl-CH₂—,F-cyclohexenyl-CH₂—, tetrahydrofuranyl-CH₂—, tetrahydropyranyl-CH₂—,fluoro-benzyl, CH₃—O-benzyl, cyano-benzyl, methyl-benzyl, chloro-benzyl,oxo-tetrahydrofuranyl-CH₂—, oxo-pyrrolidinyl-CH₂—, pyridinyl-CH₂—,pyrazinyl-CH₂—, pyrimidinyl-CH₂—, CH₃-pyrazolyl-CH₂—, CH₃-oxazolyl-CH₂—,CH₃-isoxazolyl-CH₂—, CH₃-oxadiazolyl-CH₂—, CH₃-thiazolyl-CH₂—, andCH₃-thiadiazolyl-CH₂—; R² is selected from the group consisting of H,NR⁴R⁵—C(O)—CR⁶R⁷—, CR⁸R⁹R¹⁰—, (CH₃)₂—N—CH₂—C(CH₃)₂—CH₂—,tetrahydronaphthalenyl, OH-dihydroindenyl, OH-cyclohexyl,CH₃—CH₂-pyrrolidinyl-CH₂—, oxadiazolyl-CR¹¹R¹²— optionally substitutedwith CH₃, NH₂, (CH₃)₂—N—C(O)—, CH₃—NH—C(O)—,tetrahydronaphthalenyl-NH—C(O)—, azepanyl-C(O)—,oxopyrrolidinyl(CH₂)₃—NH—C(O)—, CH₃—O—(CH₂)₂—NH—C(O)—,OH-cyclohexyl-NH—C(O)—, OH—CH₂-piperidinyl-C(O)—, CH₃—CH₂—,(CH₃)₂—CH—(CH₂)₂—NH—C(O)—, or (CH₃)₂—CH—; isoxazolyl-CR¹¹R¹²— optionallysubstituted with CH₃; furyl-CR¹¹R¹²— optionally substituted with CH₃ orCF₃: pyrazolyl-CR¹¹R¹²— optionally substituted with CH₃, (CH₃—CH—, orCH₃—CH₂—; thiazolyl-CR¹¹R¹²— optionally substituted with CH₃, CH₃—CH₂—,or CF₃; and dihydroisochromenyl-CR¹¹R¹²—; R³ is selected from the groupconsisting of H, F, Cl, bromo, difluoro, methyl, cyano, methoxy,trifluoromethyl, methylthio, methylsulfinyl, methylsulfonyl andaminosulfonyl; R⁴ and R⁵ are H, OH—(CH₂)₂—, NH₂—C(O)—(CH₂)₂—,CH₃—O—(CH₂)₂—, benzyl, pyridinyl, cyclobutyl, (CH₃)₃—C—, cyclopropyl,CH₃, OH—(CH₂)₃—, or (OH)₂—CH₂-CH—CH₂—; R⁶ and R⁷ are H, (CH₃)—C—, CH₃,benzyl, phenyl, tetrahydropyranyl, cyclohexyl, (CH₃)₂—CH—CH₂—,(CH₃)₂—CH—, or (OH)(CH₃)CH—; R⁸, R⁹ and R¹⁰ are H, (CH₃)₃—C—, NH₂—C(O)—,OH—CH₂, (CH₃CH₂)₂—N—CH₂—, CH₃, (OH) (CH₃)₂—CH—, CH₃—NH—C(O)—CH₂—,cyclopropyl-NH—C(O)—CH₂—, NH₂—C(O)—CH₂—NH—C(O)—CH₂—, or COOH—CH₂—; ortwo of R⁸, R⁹, or R¹⁰ form a cyclohexyl, and R¹¹ and R¹² are H, CH₃, or(CH₃)₃—C—.
 14. The compound of claim 13 or a pharmaceutically acceptablesalt thereof, wherein R¹ is selected from the group consisting of


15. The compound of claim 13 or a pharmaceutically acceptable saltthereof, wherein R¹ is selected from the group consisting of


16. The compound of claim 13 or a pharmaceutically acceptable saltthereof, wherein R² is selected from the group consisting of


17. The compound of claim 13 or a pharmaceutically acceptable saltthereof, wherein R² is selected from the group consisting of


18. The compound selected from the group consisting ofN-[1-aminocarbonyl)cyclohexyl]-8-(cyclohexylmethyl)-5-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1R)-1-(aminocarbonyl)-3-methylbutyl]-3-(cyclohexylmethyl)-5-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;Nalpha-{[3-(cyclohexylmethyl)-5-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}-L-phenylalaninamide;N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-3-(cyclohexylmethyl)-5-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-3-methylbutyl]-3-(cyclohexylmethyl)-(methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(cyclohexylmethyl)-7-fluoro-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-5-cyano-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamideN-[(1S)-2-amino-1-cyclohexyl-2-oxoethyl]-3-cyclohexylmethyl)-5-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S,2R)-1-(aminocarbonyl)-2-hydroxypropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;2-oxo-N-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-2-amino-2-oxo-1-phenylethyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;Nalpha-{[2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}-L-phenylalaninamide;N-[(1S)-1-(aminocarbonyl)-3-methylbutyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S,2S-2-hydroxycyclohexyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide,N-[(1S)-1-(hydroxymethyl)2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[3-(dimethylamino)-2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-2-amino-1-cyclohexyl-2-oxoethyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-t-carboxamide;3-methyl-N-{[2-oxo-3-(tetrahydro-2H-pyranyl-4-methyl)-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}-L-valine;3-hydroxy-N-{[2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}-L-valine;N-[(1S)-1-(aminocarbonyl)-2-hydroxy-2-methylpropyl]-2-oxo-3-(tetrahydro-2H-pyranyl-4-methyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-2-hydroxy-1-(hydroxymethyl)-2-methylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1R)-2-hydroxy-1-(hydroxymethyl)-2-methylpropyl]-2-oxo-3-tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-fluoro-2-oxo-3-(tetrahydro-2H-pyranyl-4-methyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;(3R)-4,4-dimethyl-3-({[2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}amino)pentanoicacid;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-butyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-(4,4,4-trifluorobutyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-5,6-difluoro-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1R)-1-(2-amino-2-oxoethyl)-2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-{(1R)-1-[2-(cyclopropylamino)-2-oxoethyl]-2,2-dimethylpropyl}-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1R)-1-{2-[2-amino-2-oxoethyl}amino]-2-oxoethyl)-2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-{(1S)-1-[(cyclopropylamino)carbonyl]-2,2-dimethylpropyl}-2-oxo-3(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-{(1S)-1-[(tert-butylamino)carbonyl]-2,2-dimethylpropyl}-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-{(1S)-1-[(cyclobutylamino)carbonyl]-2,2-dimethylpropyl}-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;5-fluoro-N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;3-methyl-N-{[2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}L-valylglycinamide;N-{(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl}-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[(4-fluorocyclohex-3-en-1-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide(diastereomer 1);N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[(4-fluorocyclohex-3-en-1-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide(diastereomer 2);N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[(4,4-difluorocyclohexyl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-5-bromo-3-(cyclohexylmethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;5-bromo-3-(cyclohexylmethyl)-N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-{(1R)-2,2-dimethyl-1-[2-(methylamino)-2-oxoethyl]propyl}-2-oxo-3-tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-{(1S)-1-[(cyclopropylamino)carbonyl]-2,2-dimethylpropyl}-5-fluoro-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(2,5-dimethyl-3-furyl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(5-methylisoxazol-3-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[2-(dimethylamino)-2-oxoethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-[2-(ethylamino)-2-oxoethyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(2-cyclopropyl-2-oxoethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(3,3-dimethyl-2-oxobutyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-{[(3-hydroxypropyl)amino]carbonyl}-2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(5-amino-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-{[5-methyl-2-(trifluoromethyl)-3-furyl]methyl}-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(5-{[4-(hydroxymethyl)piperidin-1-yl]carbonyl}-1,2,4-oxadiazol-3-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(5-{[(3-methylbutyl)amino]carbonyl}-1,2,4-oxadiazol-3-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(5-isopropyl-1,2,4-oxadiazol-3-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-N-[(1,3,5-trimethyl-1H-pyrazolyl)methyl]-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-(1,3-oxazol-4-ylmethyl)-2-oxo-3-(tetrahydro-2H-pyranylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(5-ethyl-1,2,4-oxadiazol-3-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(2-ethyl-1,3-thiazol-4-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-(3-furylmethyl)-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(5-{[(3,4-dihydro-1H-isochromen-1-ylmethyl)amino]carbonyl}-1,2,4-oxadiazol-3-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-{[5-(azepan-1-ylcarbonyl)-1,2,4-oxadiazol-3-yl]methyl}-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;2-oxo-N-{[5-({[3-(2-oxopyrrolidin-1-yl)propyl]amino}carbonyl)-1,2,4-oxadiazol-3-yl]methyl}-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;2-oxo-N-({5-[(1,2,3,4-tetrahydronaphthalen-1-ylamino)carbonyl]-1,2,4-oxadiazol-3-yl}methyl)-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-({5-[(dimethylamino)carbonyl]-1,2,4-oxadiazol-3-yl}methyl)-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(5-{[(2-methoxyethyl)amino]carbonyl}-1,2,4-oxadiazol-3-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-({5-[(methylamino)carbonyl]-1,2,4-oxadiazol-3-yl}methyl)-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1-isopropyl-1H-pyrazolyl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1,3-dimethyl-1H-pyrazol-4-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(2-methyl-1,3-thiazolyl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(5-{[(trans-4-hydroxycyclohexyl)amino]carbonyl}-1,2,4-oxadiazol-3-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-({[(2S)-2,3-dihydroxypropyl]amino}carbonyl)-2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(5-amino-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropyl]-5-fluoro-2-oxo-3(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-benzyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[2-methyl-4-(trifluoromethyl)-1,3-thiazol-5-yl]methyl)-2-oxo-3-tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[1-(2-methyl-1,3-thiazol-4-yl)ethyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-{[(2R)-5-oxotetrahydrofuran-2-yl]methyl}-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(5-amino-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropyl]-2-oxo-3-{[(2R)-5-oxotetrahydrofuran-2-yl]methyl}-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-{[(3-hydroxypropyl)amino]carbonyl}-2,2-dimethylpropyl]-2-oxo-3-{[(2R)-5-oxotetrahydrofuran-2-yl]methyl}-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-2-oxo-3-{[(2R)-5-oxotetrahydrofuran-2-yl]methyl}-2,3-dihydro-1H-benzimidazole-1-carboxamide;5-fluoro-N-[(1S)-1-{[(3-hydroxypropyl)amino]carbonyl}-2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;5-fluoro-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(2-fluorobenzyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(5-amino-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropyl]-3-benzyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;3-benzyl-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;3-benzyl-N-[(1S)-1-{[(3-hydroxypropyl)amino]carbonyl}-2,2-dimethylpropyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-aminocarbonyl)-2-(2-dimethylpropyl]-3-(3-fluorobenzyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(4-fluorobenzyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-(tetrahydro-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-2-oxo-3-pentyl-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-benzyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-(aminocarbonyl)-2,2-dimethylpropyl]-3-(2-fluorobenzyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(5-amino-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropyl]-3-benzyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;3-benzyl-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;3-benzyl-N-[(1S)-{[3-hydroxypropyl)amino]carbonyl}-2,2-dimethylpropyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(4-cyanobenzyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(2-cyanobenzyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(3-fluorobenzyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-[(1S)-1-(aminocarbonyl)-2,2-dimethylpropyl]-3-(4-fluorobenzyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;3-(4-fluorobenzyl)-N-[(1S)-1-{[(2-hydroxyethyl)amino]carbonyl}-2,2-dimethylpropyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;3-(4-fluorobenzyl)-N-[(1S)-1-{[(3-hydroxypropyl)amino]carbonyl}-2,2-dimethylpropyl]-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;N-{[3-(4-fluorobenzyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]carbonyl}-3-methyl-L-valylglycinamide;andN-[(1S)-1-(5-amino-1,3,4-oxadiazol-2-yl)-2,2-dimethylpropyl]-3-(4-fluorobenzyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;or a pharmaceutically acceptable salt thereof.
 19. A method for thetreatment of a condition mediated by CB1 receptor activity in amammalian subject including a human, which comprises administering to amammal in need of such treatment a therapeutically effective amount of acompound or pharmaceutically acceptable salt thereof of Formula I. 20.The method of claim 19, wherein said condition is selected from thegroup consisting of inflammatory pain, nociceptive pain, neuropathicpain, fibromyalgia, chronic low back pain, visceral pain, acute cerebralischemia, pain, chronic pain, acute pain, post herpetic neuralgia,neuropathies, neuralgia, diabetic neuropathy, HIV-related neuropathy,nerve injury, rheumatoid arthritic pain, osteoarthritic pain, back pain,cancer pain, dental pain, fibromyalgia, neuritis, sciatica,inflammation, neurodegenerative disease, spasticity, epilepsy,Tourette's syndrome, Parkinson's disease, neuroprotection, anxiety,cough, broncho constriction, irritable bowel syndrome (IBS),Inflammatory bowel disease (IBD), colitis, cerebrovascular ischemia,cachexia, nausea, emesis, chemotherapy-induced emesis, rheumatoidarthritis, asthma, Crohn's disease, ulcerative colitis, asthma,dermatitis, seasonal allergic rhinitis, gastroesophageal reflux disease(GERD), constipation, diarrhea, functional gastrointestinal disorder,cutaneous T cell lymphoma, multiple sclerosis, osteoarthritis,psoriasis, systemic lupus erythematosus, diabetes, glaucoma,osteoporosis, glomerulonephritis, renal ischemia, nephritis, hepatitis,cerebral stroke, vasodilation, hypertension, vasculitis, myocardialinfarction, cerebral ischemia, reversible airway obstruction, adultrespiratory disease syndrome, chronic obstructive pulmonary disease(COPD), cryptogenic fibrosing alveolitis and bronchitis.